Chemical process for preparing phenylpiperidinyl indole derivatives

ABSTRACT

The present invention relates to a method of synthesizing a compound of formula (I) also referred to as 4-(((2S,4S)-(4-ethoxy-1-(((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid, or a pharmaceutically acceptable salt thereof, and/or intermediates thereof, their use as pharmaceuticals and pharmaceutical compositions and the use of intermediates for preparing a compound of formula (I), or a pharmaceutically acceptable salt thereof.

FIELD OF THE INVENTION

The present invention relates to processes, process steps andintermediates useful in the preparation of phenylpiperidinyl indolederivatives. In particular, the present invention is in the field oforganic synthesis and is directed to a method of synthesizing a compoundof formula (I), also referred to as4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoicacid, or a pharmaceutically acceptable salt thereof, and/orintermediates thereof, methods for further preparing pharmaceuticalcompositions of the compound of formula (I), or its intermediates, theuse of intermediates for preparing a compound of formula (I) and theintermediates themselves.

BACKGROUND OF THE INVENTION

The present invention relates to a process for the preparation ofphenylpiperidinyl indole derivatives. More particularly, the presentinvention relates to a process for the preparation of the compound offormula (I)

also referred to as4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoicacid, or a pharmaceutically acceptable salt thereof, which is capable ofinhibiting the activation of the alternative pathway of the complementsystem. The complement system plays a major role in the innate andadaptive immunity system and comprises a group of proteins that arenormally present in an inactive state. These proteins are organized inthree activation pathways: the classical, the lectin, and thealternative pathways (Holers, In Clinical Immunology: Principles andpractice, ed. R. R. Rich, Mosby Press; 1996, 363-391). Molecules frommicroorganisms, antibodies or cellular components can activate thesepathways resulting in the formation of protease complexes known as theC3-convertase and the C5-convertase. The classical pathway is acalcium/magnesium-dependent cascade, which is normally activated by theformation of antigen-antibody complexes. It can also be activated in anantibody-independent manner by the binding of C-reactive proteincomplexed to ligand and by many pathogens including gram-negativebacteria. The alternative pathway is a magnesium-dependent cascade,which is activated by deposition and activation of C3 on certainsusceptible surfaces (e.g. cell wall polysaccharides of yeast andbacteria, and certain biopolymer materials). The alternative pathway(AP) utilizes C3 fragments (C3b) to opsonize the pathogens hencetargeting them for phagocytosis without the need for antibodies.Hyperactivity of the complement system, and in particular in its AP,plays a role in a large number of complement-driven diseases, such as C3glomerulopathy (C3G), paroxysmal nocturnal hemoglobinuria (PNH) and IgAnephropathy (IgAN). Phenylpiperidinyl indole derivatives, such ascompound of formula (I), or a pharmaceutically acceptable salt thereof,play a role in the inhibition of complement factor B, a known criticalenzyme for activation of the alternative complement pathway (Lesavre etal J. Exp. Med. 1978, 148, 1498-1510; Volanakis et al New Eng. J. Med.1985, 312, 395-401), which may also be a suitable target for theinhibition of the amplification of the complement pathways. Thephenylpiperidinyl indole derivatives, such as compound of formula (I),or a pharmaceutically acceptable salt thereof, and a method forpreparing such derivatives, are described in WO2015/009616. Inparticular, compound of formula (I) is described in example 26, ofWO2015/009616. One of the drawbacks of the synthesis was the use ofhazardous chemicals (such as sodium hydride, or dimethylacetamide, whichrepresent safety concerns on a larger scale) and the poor enantio- anddiastereo-selectivity of the steps, leading to unwanted stereoisomers.

Thus, there is a need to provide an alternative reaction route in aprocess for producing compound of formula (I), or a pharmaceuticallyacceptable salt thereof, generating less by-products, and easier tohandle on a large scale.

SUMMARY OF THE INVENTION

Chemical processes are usually carried out on a small scale in aresearch/early development phase, and the scale successively increasesin late phase development to finally reach the full size productionscale. Upon scaling up a process, topics related to process safety arebecoming more and more important, such as health hazards while handlinglarge amount of hazardous and/or toxic chemicals, or environmentalhazards.

Surprisingly, it was found that the compound of formula (I), or apharmaceutically acceptable salt thereof, also referred to as4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoicacid, or a pharmaceutically acceptable salt thereof, and theintermediates thereof, can be prepared with a shorter, cost efficientand safer method. Therefore, the present invention is directed to a newsynthesis of compound of formula (I) and its intermediates, using lesshazardous chemicals and/or reaction conditions, generating lessby-product and providing a reproducible process that is easier to handleon a larger scale, a process that involves fewer reactions steps, thusmore efficient, and generates high quality compounds.

In one embodiment, the invention provides a process for preparing acompound of formula (C15), or a salt thereof, as disclosed herein, saidprocess comprising the step of reacting a compound of formula (II), or asalt thereof, as disclosed herein, with a compound of formula (III), ora salt thereof, as disclosed herein, in the presence of an Iridiumcatalyst, under hydrogen pressure, optionally in the presence of anadditive, to provide the compound of formula (C15), or a salt thereof.

In another embodiment, the invention provides a process for preparing acompound of formula (S)-(C4), as disclosed herein, comprising reacting acompound of formula (C6) with an aryl-boronyl compound of formula (C7),as disclosed herein, in the presence of a catalyst, and a ligand, toobtain the compound of formula (S)-(C4).

In another embodiment, the invention provides a process for preparing acompound of formula (S)-(C5), as disclosed herein, the processcomprising the steps of:

-   (i) preparing a compound of formula (S)-(C4), as disclosed herein,    according to the process described herein; and-   (ii) treating the compound of formula (S)-(C4), obtained from step    (i), under reductive enzymatic conditions, as disclosed herein;    to obtain the compound of formula (S)-(C5).

In another embodiment, the invention provides a process for preparing acompound of formula (S)-(C9), as disclosed herein, the processcomprising the steps of

-   (i) reacting the alcohol of the compound of formula (S)-(C5), as    defined herein, with an oxygen protecting group P₂, to obtain a    compound of formula (S)-(C8), as disclosed herein,-   (ii) reacting the protected alcohol of the compound of formula    (S)-(C8) with an ethylating reagent such as    2,4,6-trimethyl-1,3,5-trioxane;    to obtain a compound of formula (S)-(C9).

In another embodiment, the invention provides a compound of formula(C13), as disclosed herein.

In another embodiment, the invention provides a process for preparing acompound of formula (C13), as disclosed herein, the process comprisingthe steps of reacting a compound of formula (C12), as disclosed herein,with a Grignard reagent, in the presence of an aldehyde source, toobtain the compound of formula (C13).

In another embodiment, the invention provides a process for preparing acompound of formula (III), or a salt thereof, as disclosed herein, theprocess comprising reacting the compound of formula (C13), with aninorganic base, in the presence of an methylating agent, to obtain acompound of formula (III), or a salt thereof.

In another embodiment, the invention provides a process for preparing acompound of formula (III), or a salt thereof, as disclosed herein, theprocess comprising the steps of:

-   (i) preparing the compound of formula (C13), as disclosed herein;    and-   (ii) further reacting the compound of formula (C13), as disclosed    herein;    to obtain the compound of formula (III), or a salt thereof.

In another embodiment, the invention relates to the use of a compound offormula (C13), as disclosed herein, for preparing a compound of formula(I), or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention relates to a process for preparinga pharmaceutical composition, the process comprising the process, asdisclosed herein, and mixing the obtained compound of formula (I), or apharmaceutically acceptable salt thereof, with a pharmaceuticallyacceptable excipient.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 depicts the X-ray powder diffraction pattern for the maleic saltof methyl 4-((2S,4S)-4-ethoxypiperidin-2-yl)benzoate (maleic salt ofCompound of formula (II)).

DETAILED DESCRIPTION OF THE INVENTION

Increasing the amount of reactants and solvents in order to scale up aprocess to a full size commercial production may be associated withlower yields, or some safety issues while handling large amount ofhazardous and/or toxic chemicals.

Surprisingly, it was found that modifying the process, as described inWO2015/009616, to synthesize compound of formula (I), or apharmaceutically acceptable salt thereof, and its syntheticintermediates, in a way as disclosed herein provides a scalable methodthat can safely be handled on a larger scale, with reproducible yields,using less hazardous/toxic chemicals. In addition, this process providesthe desired compound with high enantio- and diastereo-selectivity andproduces compound of formula (I), or a pharmaceutically acceptable saltthereof, in fewer synthetic steps. A summary of the overall process isshown in Scheme 1, vide infra.

1. Asymmetric Synthesis of Compound of Formula (II):(C1)->(C6)->(S)-(C4)->(S)-(C5)->(II).

One aspect of the present invention relates to an asymmetric process forpreparing a compound of formula (II), or salt thereof, as outlined inScheme 2 below, wherein the stereocenters in position 2 and in position4 on the piperidine are obtained in high enantio- anddiastereo-selectivity.

1.1. Synthesis of Compound of Formula (S)-(C4)

In one embodiment, the present invention relates to a process forpreparing a compound of formula (S)-(C4), as defined below, comprisingthe step of reacting a compound of formula (C6) with an aryl-boronylcompound of formula (C7), in the presence of a catalyst, and a ligand,to obtain the compound of formula (S)-(C4), as defined in Scheme 3,

whereinP₁ is a nitrogen protecting group, for example, selected from the groupconsisting of tert-butyloxycarbonyl (Boc), benzyl (Bz),benzyloxycarbonyl (Cbz), and allyloxycarbonyl (Alloc), preferably thenitrogen protecting group is benzyloxycarbonyl (Cbz); and R isC₁-C₆alkyl, preferably R is methyl.

The intermediate compound of formula (C6), as described in Scheme 3, canbe prepared according to any literature and textbooks available to theskilled person in the art. For example, compound of formula (C6) can beprepared from a compound of formula (C1) as disclosed in Scheme 1 (e.g.following Knapp et al J. Org. Chem. 2005, 70(19), 7715, firstexperimental procedure on page 7718).

The catalyst used for the enantioselective conjugate addition between acompound of formula (C6) and an aryl-boronyl compound of formula (C7),as described in Scheme 3, can be selected, for example, from the groupconsisting of Rh(acac)(C₂H₄)₂, Rh(nbd)₂BF₄, Rh(COD)BF₄, Rh(acac)(COD),[Rh(COD)Cl]₂, [Rh(COD)OMe]₂, [Rh(MeCN)₂(COD)]BF₄, [RhCl(S)-BINAP]₂,[Rh(OH)((S)-BINAP)]₂, (NHC—Pd(II)), and Pd(O₂CCF₃)₂. The reaction asdescribed in Scheme 3 is best performed in the presence of a rhodiumcatalyst. Preferably, the catalyst is selected from the group consistingof Rh(acac)(C₂H₄)₂, Rh(nbd)₂BF₄, and Rh(COD)BF₄. Most preferably, thecatalyst is Rh(acac)(C₂H₄)₂. The catalyst can be present in an amountbelow 15 mol % respective to the amount of compound of formula (C6).Typically, the catalyst may be present in an amount below 5 mol %. Mostpreferably, the catalyst may be present in an amount from 0.01 mol % to2 mol %.

The ligand used to perform the reaction, as depicted in Scheme 3, can beselected from the group consisting of (S)-BINAP((S)-(2,2′-bis(diphenylphosphino)-1,1′-binaphthyl)), (S)-Tol-BINAP((R)-(+)-2,2′-Bis(di-p-tolylphosphino)-1,1′-binaphthyl), (S)-SDP((S)-(−)-7,7′-Bis(diphenylphosphino)-2,2′,3,3′-tetrahydro-1,1′-spirobiindene), (R)-SegPhos((R)-(+)-5,5′-Bis(diphenyl phosphino)-4,4′-bi-1,3-benzodioxole),(R)-(+)-MeO-BIPHEP((R)-(+)-(6,6′-Dimethoxybiphenyl-2,2′-diyl)bis(diphenylphosphine)),(S,S)-Me-Ferrocelane (1,1′-Bis[(2S,5S)-2,5-dimethylphospholano]ferrocene), chiral Josiphos ligand, (S)-(−)XylBINAP(1,1′-Binaphthalene-2,2′-diylbis[bis(3,5-dimethylphenyl)phosphine]),(S,S)-Me-DUPHOS ((+)-1,2-Bis[(2S,5S)-2,5-dimethylphospholano] benzene),(S,S)-Et-DUPHOS ((+)-1,2-Bis[(2S,5S)-2,5-diethylphospholano] benzene),(R,R)-iPr-DUPHOS(((+)-1,2-Bis[(2S,5S)-2,5-diisopropylphospholano]benzene)), and(R,R)-Ph-BPE ((+)-1,2-Bis((2R,5R)-2,5-diphenylphospholano)ethane).Preferably, the ligand is selected from the group consisting of(S)-(−)XylBINAP, (S,S)-Me-DUPHOS, (S,S)-Et-DUPHOS, (R,R)-Ph-BPE, ormixtures thereof. More preferably, the ligand is selected from the groupconsisting of (S)-(−)XylBINAP, (R,R)-Ph-BPE, or mixtures thereof. Theligand can be present in a range from about 0.005 mol % to about 5 mol%, respective to the amount of compound of formula (C6). Mostpreferably, the ligand may be present in an amount from about 0.01 mol %to about 3 mol %. Typically, the ligand is present in an amount below 2mol %.

The reaction described in Scheme 3 can be performed in a solventselected from, for example, 1,4-dioxane, tetrahydrofuran (THF), 2-methyltetrahydrofuran, diethyl ether, toluene, dimethylformamide (DMF),dimethylacetamide (DMA), water, methanol, ethanol, n-propanol,2-propanol, n-butanol, 2-butanol, tert-butanol, tert-amyl alcohol,cyclopentyl methyl ether (CPME), or mixtures thereof. The preferredsolvent of the reaction is one or more solvents selected fromdimethylformamide (DMF), tert-amyl alcohol, toluene, cyclopentyl methylether (CPME), tetrahydrofuran (THF), 2-methyl tetrahydrofuran, water, ormixtures thereof. Most preferably, the solvent is a mixture of tert-amylalcohol and water. The ratio (volume to volume) of said mixture may bein the range from 20:1 to 1:20. Most preferably, the ratio is in therange from 15:1 to 10:1. Typically, the ratio is about 10:1, such thatthere is an excess of tert-amyl alcohol over water.

The substituents X₁ and X₂ on the aryl-boronyl compound of formula (C7),can be identical or different, and can be halogen, hydroxy, C₁-C₄alkoxy,hydrogen or C₁-C₁₂alkyl. The substituents X₁ and X₂ can also be bridgedtogether in a cyclic manner, for example X₁, X₂ combined are alkylenewhich together with the boron and the oxygen atoms form a 5- or6-membered ring, for example to form a diol residue. For example theboron group B(X₁)(X₂) on the compound of formula (C7) is selected fromthe group consisting of B(OH)₂, —B(OC(CH₃)₂C(CH₃)₂O), and 9-BBN.Preferably, B(X₁)(X₂) is B(OH)₂. The aryl-boronyl compound of formula(C7) can be commercially available, or can be prepared from commerciallyavailable starting material according to any literature and textbooksavailable to the skilled person in the art.

Optionally, the reaction, as described in Scheme 3, can be performed inthe presence of a base. The base can be, for example, sodium carbonate,potassium carbonate, cesium carbonate, sodium bicarbonate, potassiumbicarbonate, sodium acetate, potassium acetate, trisodium phosphate,potassium phosphate, lithium hydroxide, sodium hydroxide, potassiumhydroxide, cesium hydroxide, barium hydroxide, sodium methoxide,potassium methoxide, sodium ethoxide, potassium ethoxide, triethylamine,N,N-diisopropylethylamine (DIPEA), sodium tertbutoxide, potassiumtertbutoxide, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),1,4-diazabicyclo[2.2.2]octane (DABCO), potassium fluoride or cesiumfluoride.

The reaction as described in Scheme 3 is advantageously performed whenthe nitrogen protecting group P₁ is benzyloxycarbonyl (Cbz), thearyl-boronyl compound of formula (C7) is4-(methoxycarbonyl)phenyl)boronic acid (B(OH)₂), the catalyst isRh(acac)(C₂H₄)₂, and the ligand is (S)-(−)XylBINAP or (R,R)-Ph-BPE.Preferably, the reaction is performed at a temperature between about 25°C. to about 85° C., more preferably between about 40° C. to about 70° C.Most preferably, the reaction is performed at a temperature betweenabout 50° C. to about 60° C. Performing the reaction under thoseconditions is particularly advantageous as the reaction is highlyefficient, the enantioselectivity is enhanced thus by-product formationis reduced. The enantioselectivity is between 84% to more than 99% ee.Thus the present step is especially suitable for large-scalemanufacture. Furthermore, it was surprisingly found that the ligandsused in the catalytic arylation, as described herein, can significantlyenhance the performance in both reactivity and selectivity, leading to ahighly enantioselective arylation.

In another embodiment, the reaction as depicted in Scheme 3 isadvantageously performed when the catalyst, as disclosed herein, and theligand, as disclosed herein, are mixed together to form a new activereagent prior to be introduced into the reaction mixture. In oneembodiment, the new active reagent is a catalyst-ligand complex. Thecatalyst-ligand complex can be, for example, but not limited to,(R,R)-Ph-BPE-Rh(Acac) or (S)-XylBINAP-Rh(Acac). It was surprisinglyfound that mixing the catalyst and the ligand to form a complex isadvantageous when the reaction is performed in the presence of an airsensitive catalyst. The new catalyst-ligand complex has the advantage tobe more active and less air sensitive. Thus, lower amounts of catalystare needed to perform the reaction, as depicted in Scheme 3, in highyield.

In one embodiment, the compound of formula (I), or a pharmaceuticallyacceptable salt thereof, can be prepared via a process comprising thesteps of preparing a compound of formula (S)-(C4) by reacting a compoundof formula (C6) with an aryl-boronyl compound of formula (C7) in thepresence of a catalyst and a ligand, to obtain the compound of formula(S)-(C4), as defined in Scheme 3.

1.2. Synthesis of Compound of Formula (S)-(C5)

In another embodiment, the present invention relates to a process forpreparing a compound of formula (S)-(C5), as defined herein below, theprocess comprising the steps of:

-   -   (i) preparing a compound of formula (S)-(C4) according to the        process of Section 1.1; and    -   (ii) treating the compound of formula (S)-(C4), obtained from        step (i), under reductive enzymatic conditions;        to obtain the compound of formula (S)-(C5), as defined in Scheme        4.

wherein R is C₁-C₆alkyl, preferably R is methyl; andwherein P₁ is a nitrogen protecting group, as defined above in Section1.1.

The reductive enzymatic conditions, as disclosed herein, comprisetreating a compound of formula (S)-(C4) with an enzyme, a co-factor, inan aqueous buffer solution, optionally in the presence of a surfactant,to provide a compound of formula (S)-(C5), as defined herein. In oneembodiment, the reductive enzymatic conditions are enzymatic catalyzedconditions.

The enzyme used to perform the reaction outlined in Scheme 4, is anyenzyme suitable to perform the above transformation. Suitable enzymesfor use in the present reaction mixture include, for example,ketoreductases (KRED), alcohol dehydrogenases, glucose dehydrogenase(GDH), or mixtures thereof. Preferably, the enzyme is a ketoreductase(KRED). Optionally, the reaction can comprise a second enzyme, so-calledco-enzyme, for example, glucose dehydrogenase (GDH). Suitableketroreductase (KRED) used in the present invention were purchased fromCodexis Inc. (Codex® KRED screening kit), and are described e.g. in WO2005/017135, WO 2008/103248, WO2009/029554, WO2009/036404,WO2016/130412, and WO2018/013710. The KRED-EW124 enzyme was purchasedfrom Enzyme Works Inc. China. Suitable ketoreductase can be selectedfrom, for example, but not limited to, the group consisting ofKRED-EW124, KRED-P3-G09, KRED-P1-B02, KRED-P1-C01, KRED-P2-B02,KRED-P2-C02, KRED-P3-B03, KRED-P2-D03, KRED-P2-D11, KRED-P2-D12,KRED-P2-H07, KRED-P3-H12, KRED-101, KRED-119, or mixtures thereof.Preferably, the ketroreductase (KRED) is selected from KRED-EW124,KRED-P3-G09, or mixtures thereof.

The enzyme is present in the reaction mixture in a concentrationsuitable to perform the reaction as outlined in Scheme 4, for example inan amount of about 0.01% to about 100% relative to the amount ofcompound of formula (S)-(C4). In particular, the enzyme may be presentin an amount of about 0.1% to about 75%, about 0.5% to about 50%, about1% to about 40%, about 2% to about 30%, about 4% to about 25% or about5% to about 20%, relative to the amount of the compound of formula(S)-(C4).

The reaction as outlined in Scheme 4, further comprises a co-factor. Thepresence and type of the co-factor depends on the enzymatic reaction,which is to be performed. The co-factor can be selected, for example,from the group consisting of nicotinamide adenine dinucleotide (NAD),nicotinamide adenine dinucleotide phosphate (NADP), flavin adeninedinucleotide (FAD), pyridoxal monophosphate, or mixtures thereof. Theco-factor may be used to provide protons, or electrons for the enzymaticreaction. In another aspect, the co-factor may be present in thereaction mixture in an ionic form, such as, for example, NAD+, NADP+. Inanother aspect, the co-factor may be present in the reaction mixture ina protonated form, such as, for example, NAD-H, NADP-H, or NADP-Na. Inanother aspect, the reaction is an enzymatic catalyzed reaction. Forexample, the reaction mixture may comprise a further enzyme, so calledco-enzyme, which regenerates the co-factor. For example, if NAD, NADP orFAD is used as co-factor, the aqueous reaction mixture may furthercomprise a dehydrogenase such as an alcohol dehydrogenase, or a glucosedehydrogenase, and a respective substrate such as an alcohol or glucose.The co-factor may be present in the aqueous reaction mixture instoichiometric amounts. For example, the molar amount may be at least ashigh as the molar amount of the compound of formula (S)-(C4). In anotheraspect, the amount of co-factor is lower than the amount of the compoundof formula (S)-(C4), in particular in the range from about 0.01% toabout 20%, about 0.05% to about 15%, about 0.1% to about 10%, about0.25% to about 7.5%, or about 0.5% to about 5% relative to the amount ofthe compound of formula (S)-(C4).

The reaction as outlined in Scheme 4, is performed in an aqueous buffersolution. The buffer solution should be suitable to keep the pH of thereaction mixture at, or about, a neutral pH. The aqueous reactionmixture preferably has a pH at which the enzyme is active and stable,and which is suitable for the enzymatic reaction. In certainembodiments, the pH value is in the range from about 6.0 to about 8.0.More preferably, the pH is from about 6.5 to about 7.5, such as about7.0. The buffer can be selected from the group consisting of2-Amino-2-(hydroxymethyl)propane-1,3-diol (TRIS),4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES),3-(N-morpholino)propanesulfonic acid (MOPS),piperazine-N,N′-bis(2-ethanesulfonic acid (PIPES), borate, glycine,triethanol amine, phosphate, citrate, acetate and ammonia. Moreparticularly, the buffer solution is a phosphate buffered saline (PBS)solution.

The reaction as described in Scheme 4 may also be performed in thepresence of a surfactant. Suitable surfactant can be selected, forexample, from vitamin E, tocopherol, α-tocopherol, and tocopherolpolyethylene glycol succinates (TPGS). In particular, the surfactant isTPGS. Suitable tocopherol polyethylene glycol succinates (TPGS)surfactant can be selected, for example, but not limited to, fromDL-α-tocopherol polyethylene glycol succinates such as TPGS-750-M,TPGS-1000, TPGS-1500, TPGS-400, TPGS-1100-M, TPGS-2000, TPGS-860-oleate,TPGS-PEG-PPG-PEG-1100, and TPGS-PPG-PEG-70-butyl; and DL-α-tocopherolpolypropylene glycol succinates such as TPPG-1000 and TPPG-1000-butyl;and polyethylene glycol α-tocopherol diester of sebacic acid (PTS) suchas PTS-600. Preferably, the surfactant is selected from the groupconsisting of TPGS-750-M, TPGS-1000 and PTS. Most preferably, thesurfactant is TPGS-750-M.

The reaction as described in Scheme 4 is advantageously performed whenthe enzyme is a ketoreductase (KRED), the co-factor is nicotinamideadenine dinucleotide phosphate (NADP), preferably NADP-Na, in an aqueousbuffer solution comprising a surfactant. In particular, the reaction isperformed particularly well when the buffer solution is a mixture of aphosphate buffered saline (PBS) solution comprising a TPGS-750-Msurfactant. Preferably, the reaction is performed at a temperaturebetween about 30° C. to about 90° C., more preferably between about 40°C. to about 70° C. Most preferably, the reaction is performed at atemperature of about 50° C. Performing the reaction under thoseconditions is particularly advantageous as the reaction provides anenvironmentally friendly and scalable method of reducing a ketone intoan alcohol, as the reaction is performed in aqueous media. Furthermore,the reaction is diastereoselective providing the desired alcohol in highyield, thus avoiding mixtures of diastereoisomers as by-products.

In one embodiment, the compound of formula (I), or a pharmaceuticallyacceptable salt thereof, can be prepared via the process comprising thesteps of reacting a compound of formula (S)-(C4) using an enzyme, aco-factor and optionally a co-enzyme, in an aqueous buffer solution,optionally in the presence of a surfactant, to provide a compound offormula (S)-(C5), and reacting further the compound of formula (S)-(C5)to obtain the compound of formula (I), or a pharmaceutically acceptablesalt thereof.

In another embodiment, the invention provides a useful intermediate forthe synthesis of a compound of formula (II), or a salt thereof, acompound of formula (S)-(C5):

wherein R is C₁-C₆alkyl, preferably R is methyl; and P₁ is a nitrogenprotecting group, as defined above in Section 1.1.

In another embodiment, the invention provides the use of a compound offormula (S)-(C5) for preparing a compound of formula (II), or a saltthereof.

In another embodiment, the invention provides the use of a compound offormula (S)-(C5) for preparing a compound of formula (I), or apharmaceutically acceptable salt thereof.

1.3. Synthesis of Compound of Formula (II), or a Salt Thereof

In another embodiment, the invention provides a process for preparing acompound of formula (S)-(C9), as outlined in Scheme 5, the processcomprising the steps of:

-   (i) reacting the alcohol of the compound of formula (S)-(C5), with    an oxygen protecting group P₂, to obtain a compound of formula    (S)-(C8),-   (ii) reacting the protected alcohol of the compound of formula    (S)-(C8) with an ethylating reagent, such as    2,4,6-trimethyl-1,3,5-trioxane;    to obtain a compound of formula (S)-(C9).

wherein R is C₁-C₆alkyl, preferably methyl;wherein P₁ is a nitrogen protecting group as defined above in Section1.1; andwherein P₂ is an oxygen protecting group. Preferably, the oxygenprotecting group P₂ is a silyl group selected, for example, from thegroup consisting of tert-butyldimethylsilyl (TBS), trimethylsilyl (TMS),triethylsilyl (TES), triisopropylsilyl (TIPS), andted-butyldiphenylsilyl (TBDPS). Most preferably P₂ istert-butyldimethylsilyl (TBS).

The alcohol group of compound of formula (S)-(C5) is protected with anoxygen protecting group P₂ in the presence of a base, in a solvent, toobtain a first intermediate of formula (S)-(C8), as outlined in Scheme6,

wherein P₂ is an oxygen protecting group, such as a silyl groupselected, for example, from the group consisting oftert-butyldimethylsilyl (TBS), trimethylsilyl (TMS), triethylsilyl(TES), triisopropylsilyl (TIPS), and tert-butyldiphenylsilyl (TBDPS).The base can be, for example, an amine base. The base can be selected,for example, from the group consisting of triethylamine, pyridine,imidazole, 2,6-lutidine, dimethylaminopyridine, or mixtures thereof.

Solvents generally known in the art can be used. The solvent isselected, for example, from the group consisting of isopropanol,ethanol, dimethylformamide, acetonitrile, tetrahydrofuran,2-methyl-tetrahydrofuran, dichloromethane (DCM), dichloroethane (DCE),toluene, heptane, or mixtures thereof.

In another embodiment, the invention provides a useful intermediate forthe synthesis of a compound of formula (II), or a salt thereof, acompound of formula (S)-(C8),

wherein R is C₁-C₆alkyl, preferably methyl;wherein P₁ is a nitrogen protecting group as defined above in Section1.1; andwherein P₂ is an oxygen protecting group. Preferably, the oxygenprotecting group P₂ is a silyl group selected, for example, from thegroup consisting of tert-butyldimethylsilyl (TBS), trimethylsilyl (TMS),triethylsilyl (TES), triisopropylsilyl (TIPS), andted-butyldiphenylsilyl (TBDPS). Most preferably P₂ istert-butyldimethylsilyl (TBS).

In another embodiment, the present invention provides for the use of acompound of formula (S)-(C8), for preparing a compound of formula (II),or a salt thereof.

In another embodiment, the present invention provides for the use of acompound of formula (S)-(C8), for preparing a compound of formula (I),or a pharmaceutically acceptable salt thereof.

In a next step, the oxygen protecting group P₂ on compound of formula(S)-(C8) is then cleaved. The resulting alcohol is reacted with anethylating reagent, in situ, to obtain an intermediate of formula(S)-(C9), as outlined in Scheme 7, vide infra.

Usually, any ethylating reagent known in the art is suitable. Examplesof suitable ethylating reagents are ethyl iodide, ethyl bromide, ethylchloride, ethyl fluoride, diethylsulphate, ethyl triflate (EtOTf),4-ethylsulfonyltoluene, 2,4,6-trimethyl-1,3,5-trioxane, and mixturesthereof. Preferably the ethylating reagent is2,4,6-trimethyl-1,3,5-trioxane.

The removal of the oxygen protecting group P₂ and alkylation of the freealcohol in situ can be carried out with Et₃SiH, an ethylating reagent,in the presence of a solvent and a Lewis acid. The Lewis acid can beselected, for example, from TESOTf, TMSBr, BiBr₃, TMSOTf, TBSOTf, ormixtures thereof. The reaction consisting of removing the oxygenprotecting group P₂ can take place in a solvent that facilitates theremoval of the oxygen protecting group and the alkylation. As anexample, the solvent can be selected from the group consisting ofdichloromethane, ethyl acetate, 1,4-dioxane, diethyl ether,tetrahydrofuran, methanol and acetonitrile. The reaction mixture isperformed at a temperature between about 0° C. to about 10° C.Preferably, between about 3° C. to about 7° C. Most preferably, betweenabout 4° C. to about 5° C.

In another embodiment, the invention relates to a process furthercomprising the step of reacting the compound of formula (S)-(C9) toremove the nitrogen protecting group P₁, to obtain the compound offormula (II), or a salt thereof, as outlined in Scheme 8 below,

wherein R is C₁-C₆alkyl, preferably methyl; andwherein P₁ is a nitrogen protecting group as defined above in Section1.1.

The removal of the nitrogen protecting group P₁ can be carried out understandard reaction conditions known in the art. Unless otherwisespecified, the nitrogen protecting group can be removed in the absenceor, customarily, in the presence of acids or bases, preferably acids orbases that cause removal of the nitrogen protecting group but at thesame time do not cause chemical degradation of the compounds.Preferably, the nitrogen protecting group is removed with an acid. Forexample, the deprotection reaction when P₁ is tert-butyloxycarbonyl(Boc) is best performed in acidic conditions. Particularly suitableacids for the removal of the nitrogen protecting group P₁ areHF.pyridine, HF.triethylamine ammonium fluoride, hexafluoroisopropanol,acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, ora combination thereof. The nitrogen protecting group P₁ can be removedin catalytic conditions in the presence of a source of hydrogen. Forexample, the deprotection reaction when P₁ is benzyl (Bz),benzyloxycarbonyl (Cbz), or allyloxycarbonyl (Alloc), is best performedin catalytic conditions in the presence of a source of hydrogen.Particularly suitable catalyst for the removal of the nitrogenprotecting group P₁ can be, for example, palladium on carbon (Pd/C), orpalladium(II) acetate (Pd(OAc)₂). The reaction consisting of removingthe nitrogen protecting group can take place in a solvent thatfacilitates the removal of the protecting group, and it is any solventthat the skilled person would select from a general textbook. As anexample, the nitrogen protecting group can be removed in a solventselected from the group consisting of dichloromethane, ethyl acetate,1,4-dioxane, diethyl ether, tetrahydrofuran, methanol, ethanol,isopropanol and acetonitrile. For example, the deprotection reaction forthe tert-butyloxycarbonyl (Boc) nitrogen protecting group is performedbest with trifluoroacetic acid in dichloromethane, optionally at ambienttemperature. For example, the deprotection reaction for thebenzyloxycarbonyl (Cbz) nitrogen protecting group is best performed withpalladium on carbon (Pd/C), under hydrogen, in isopropanol, at roomtemperature.

The reactions as described in Scheme 5 are advantageously performed whenthe alcohol on compound of formula (S)-(C5) is protected with an oxygenprotecting group P₂ which is tert-butyldimethylsilyl (TBS), in thepresence of imidazole as a base, in a mixture of acetonitrile andisopropanol, to obtain a first intermediate of formula (S)-(C8). Thenthe cleavage and replacement of the oxygen protecting group P₂ oncompound of formula (S)-(C8) by an ethyl group, to obtain anintermediate of formula (S)-(C9) is best performed in the presence ofTESOTf, Et₃SiH, 2,4,6-trimethyl-1,3,5-trioxane in acetonitrile, at atemperature between 4° C. to 5° C. Then the nitrogen protecting group P₁on compound of formula (S)-(C9) is cleaved under catalytic conditions inthe presence of palladium on carbon (Pd/C), hydrogen, in isopropanol, atroom temperature, to obtain a compound of formula (II), or a saltthereof. Performing the protection of the alcohol group of compound offormula (S)-(C5) in two steps (first protection with P₂, second removalof P₂ and addition of an ethyl group) under those conditions isparticularly advantageous as it provides reactions that are scalableavoiding any hazardous chemicals, such as sodium hydride used inWO2015/009616, without impacting the yield of the transformation. Thus,the process produces safely the compound of formula (II), or a saltthereof. In one embodiment, the compound of formula (II) is a maleicsalt.

In another embodiment, the oxygen protecting group removal and thealkylation are performed sequentially, in one pot.

In one embodiment, the process comprises the steps of:

-   -   protecting the alcohol of the compound of formula (S)-(C5) with        an oxygen protecting group P₂, to obtain a compound of formula        (S)-(C8),    -   alkylating the protected alcohol of compound of formula (S)-(C8)        with an ethyl group, to obtain a compound of formula (S)-(C9),    -   removing the nitrogen protecting group P₁, to obtain a compound        of formula (II), or a salt thereof, and    -   reacting further compound of formula (II), or a salt thereof, to        obtain the compound of formula

(I), or a pharmaceutically acceptable salt thereof.

2. Racemic Synthesis of a Compound of Formula (II):(C1)->(C3)->(C4)->(C5)->(II).

In another embodiment, the compound of formula (II), or salt thereof,can be prepared using the process as outlined in Scheme 9 below.

wherein R is C₁-C₆alkyl preferably methyl;wherein P₁ is a nitrogen protecting group selected from the groupconsisting of tert-butyloxycarbonyl (Boc), benzyl (Bz),benzyloxycarbonyl (Cbz), and allyloxycarbonyl (Alloc), preferably thenitrogen protecting group is benzyloxycarbonyl (Cbz).wherein P₂ is an oxygen protecting group selected for example, but notlimited to, from the group consisting of tert-butyldimethylsilyl (TBS),trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), andtert-butyldiphenylsilyl (TBDPS). Most preferably, P₂ istert-butyldimethylsilyl (TBS).

2.1. Synthesis of Compound of Formula (C4)

Another embodiment, the present invention relates to a process forpreparing a compound of formula (C4) comprising the steps of:

-   -   reacting a compound of formula (C1), with a compound of formula        (C2), in a solvent, in the presence of a ligand, a Grignard        reagent, and a protecting group precursor, to form a compound of        formula (C3); and    -   further reducing the double bond of compound of formula (C3) to        form the compound of formula (C4), as outlined in Scheme 10,

wherein Y is halo, wherein R is C₁-C₆alkyl, preferably methyl; andwherein P₁ is a nitrogen protecting group, as described herein.According to the invention, the preferred nitrogen protecting group P₁is selected as described above in Section 2.

The protecting group precursor used to perform the coupling reactionbetween a compound of formula (C1) and a compound of formula (C2), asoutlined in Scheme 10, is selected depending on the nitrogen protectinggroup P₁ used to perform the transformation. For example, when P₁ isbenzyloxycarbonyl (Cbz) the precursor is benzyl chloroformate (Cbz-Cl),when P₁ is benzyl (Bz) the precursor is benzoyl chloride (Bz-Cl), whenP₁ is allyloxycarbonyl (Alloc) the precursor is allyl chloroformate(Alloc-Cl), or when P₁ is tert-butyloxycarbonyl (Boc) the precursor isdi-tert-butyl dicarbonate (Boc₂O).

The ligand used to perform the reaction, as depicted in Scheme 10, canbe selected from, for example, but not limited to, the group consistingof N,N,N′,N′,N″-pentamethyldiethylenetriamine,N,N,N′,N′-tetraethylethylenediamine, bis[2-(dimethylamino)ethyl]ether,tetramethylethylene diamine, or methoxy poly(ethyleneglycol), ormixtures thereof. Preferably, the ligand isbis[2-(dimethylamino)ethyl]ether.

The Grignard reagent is, selected from, for example, the groupconsisting of MeMgBr, MeMgCl, EtMgBr, EtMgCl, iPrMgCl, iPrMgBr, ormixtures thereof. Most preferably, the Grignard reagent is iPrMgCl oriPrMgBr.

The first reaction described in Scheme 10, can be performed in a solventselected, for example, from 1,4-dioxane, 4-methyl-1,3-dioxane, diglyme,tetrahydrothiophene, 2-methyltetrahydrofuran, cyclopentylmethyl ether(CPME), diethoxymethane (DEM), toluene, tetrahydrofuran (THF), diethylether, or mixtures thereof. Preferably, the solvent is an anhydroussolvent selected from 1,4-dioxane, tetrahydrofuran (THF), diethyl ether,or mixtures thereof. Typically, the solvent is THF.

The double bond of intermediate compound of formula (C3) can be reducedto obtain a compound of formula (C4), following the method disclosed inWO2015/009616 (page 97, Intermediate 2-12-B).

The reaction as described in Scheme 10, advantageously provides acompound of formula (C3) when performed in the presence ofbenzyloxycarbonyl (Cbz) chloride as protecting group precursor, iPrMgClor iPrMgBr as Grignard reagent, and bis[2-(dimethylamino)ethyl] ether asligand. Preferably, the reaction is performed at a temperature between10° C. to 40° C., more preferably between 15° C. to 35° C. Typically,the reaction is best performed at a temperature from 20° C. to 30° C.Performing the reaction under those conditions is particularlyadvantageous as the reaction proceeds in high yield, thus making thepresent reaction suitable for large-scale manufacture.

In one embodiment, the process for preparing a compound of formula (I),or a pharmaceutically acceptable salt thereof, comprises the steps ofpreparing compound of formula (C4) by reacting a compound of formula(C1), with a compound of formula (C2), in a solvent, in the presence ofa ligand, a metallic-reagent, and a protecting group precursor, to forma compound of formula (C3), and further reducing the compound of formula(C3) to form the compound of formula (C4), as outlined in Scheme 10.

2.2. Synthesis of Compound of Formula (C5)

In one embodiment, the process for preparing a compound of formula (I),or a pharmaceutically acceptable salt thereof, as defined in Scheme 1,comprises reacting a compound of formula (C4) using an enzyme, aco-factor, in an aqueous buffer solution, optionally in the presence ofa surfactant, to provide a compound of formula (C5), or a salt thereof,as outlined in Scheme 11 below.

Another embodiment, the present invention relates to a process forpreparing a compound of formula (C5) the process comprising the stepsof:

-   (i) preparing a compound of formula (C4), as disclosed in the    process of Section 2.1; and-   (ii) treating the compound of formula (C4), obtained from step (i),    under reductive enzymatic conditions;    to obtain the compound of formula (C5), as outlined in Scheme 11    below,

wherein R is C₁-C₆alkyl, preferably methyl; andwherein P₁ is a nitrogen protecting group, as described above in Section2, preferably benzyloxycarbonyl (Cbz).

The reductive enzymatic conditions, as disclosed herein, comprisetreating a compound of formula (C4) with an enzyme, a co-factor, in anaqueous buffer solution, optionally in the presence of a surfactant, toprovide a compound of formula (C5).

Suitable enzyme, co-factor, aqueous buffer solution, and surfactant, arethe ones used to perform the reaction as described in Section 1.2. Thereaction as described in Scheme 11 is advantageously performed when theenzyme is a ketoreductase (KRED), when the co-factor is nicotinamideadenine dinucleotide phosphate (NADP), in an aqueous buffer solutioncomprising no surfactant, and optionally comprising a second enzyme socalled co-enzyme (as defined in Section 1.2). In particular, thereaction is performed particularly well when the co-enzyme is glucosedehydrogenase (GDH) and the co-factor is D-glucose. Preferably, thereaction is performed at a temperature between 30° C. to 90° C., morepreferably between 40° C. to 70° C. Most preferably, the reaction isperformed at a temperature of about 50° C.

Performing the reaction under those conditions is particularlyadvantageous as the enantioselectivity of the reduction is enhanced. Inaddition, the reaction is performed in mild conditions thus generatingless by-products. Furthermore, the reaction provides an environmentallyfriendly and scalable method of reducing a ketone into an alcohol, asthe reaction is performed in aqueous media.

2.3. Synthesis of Compound of Formula (II)

In one embodiment, the process comprises the following steps of:

-   -   protecting the alcohol of the compound of formula (C5), with an        oxygen protecting group P₂, to form a compound of formula (C8),    -   alkylating the protected alcohol on compound of formula (C8)        with an ethyl group, to obtain a compound of formula (C9),    -   removing the nitrogen protecting group P₁, to obtain a compound        of formula (II), or salt thereof, and    -   reacting further the compound of formula (II), or a salt        thereof, to obtain the compound of formula (I), or a        pharmaceutically acceptable salt thereof.

In another embodiment, the invention provides a process for preparing acompound of formula (C9), as outlined in Scheme 12 below, the processcomprising the steps of:

-   (i) reacting the alcohol of the compound of formula (C5), with an    oxygen protecting group P₂, to obtain a compound of formula (C8),-   (ii) reacting the protected alcohol of the compound of formula (C8)    with an ethylating reagent;    to obtain a compound of formula (C9),

wherein R is C₁-C₆alkyl, preferably methyl;wherein P₁ is a nitrogen protecting group. Preferably, the nitrogenprotecting group P₁ is selected from the group consisting oftert-butyloxycarbonyl (Boc), benzyl (Bz), benzyloxycarbonyl (Cbz), andallyloxycarbonyl (Alloc). Most preferably, the nitrogen protecting groupis benzyloxycarbonyl (Cbz);wherein P₂ is an oxygen protecting group. Preferably, the oxygenprotecting group P₂ is a silyl group selected, for example, but notlimited to, from the group consisting of tert-butyldimethylsilyl (TBS),trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), andtert-butyldiphenylsilyl (TBDPS). Most preferably, P₂ istert-butyldimethylsilyl (TBS).

The alcohol group of compound of formula (C5) is protected with anoxygen protecting group P₂ in the presence of a base, in a solvent, toobtain a first intermediate of formula (C8), using the same conditionsas described above for the (S)-(C5) to (S)-(C8) transformation (seeSection 1.3). In particular, the protection of compound of formula (C5)is performed particularly well when the oxygen protecting group P₂ istert-butyldimethylsilyl (TBS), the base is imidazole, in a mixture oftoluene and heptane, to obtain a first intermediate of formula (C8).

The oxygen protecting group P₂ on compound of formula (C8) is thencleaved and the resulting alcohol is reacted with an ethylating reagentto obtain an intermediate of formula (C9), using similar conditions asthe ones described above to obtain intermediate of formula (S)-(C9) (seeSection 1.3). In particular, the cleavage and replacement of the oxygenprotecting group P₂ by an ethyl group, in situ, to obtain anintermediate of formula (C9) is advantageously performed with TESOTf,Et₃SiH, and 2,4,6-trimethyl-1,3,5-trioxane, in acetonitrile, at atemperature between 4° C. to 5° C. Performing the ethylation of thealcohol group under those conditions is particularly advantageous as itprovides a scalable method avoiding any hazardous chemicals, such assodium hydride (NaH) used in WO2015/009616, without impacting the yieldof the transformation.

In another embodiment, the nitrogen protecting group P₁ on compound offormula (C9) is cleaved off, followed by a chiral resolution to obtain acompound of formula (II), or a salt thereof. The removal of the oxygenprotecting group P₁ can be carried out under standard reactionconditions, as described above in Section 1.3 ((S)-C9 to (II)). Thechiral resolution can be performed, for example, according to WO2015/009616 (for example intermediate 2-13, on pages 96-97). Thecompound of formula (II) can be present in a salt form, as describedabove, for example, the maleic salt.

3. Synthesis of a Compound of Formula (III): (C12)->(C13)->(III). 3.1.Synthesis of a Compound of Formula (C13)

In another embodiment, the invention provides a process for preparing acompound of formula (C13), the process comprising the steps of reactinga compound of formula (C12) with a Grignard reagent or with a Lewisacid, in the presence of an aldehyde source, to obtain the compound offormula (C13), as outlined in Scheme 13.

In another embodiment, the invention provides a process for preparing acompound of formula (C13), the process comprising the steps of reactinga compound of formula (C12) with a Grignard reagent, in the presence ofan aldehyde source, to obtain the compound of formula (C13), as outlinedin Scheme 13, vide-infra.

wherein P₃ is a nitrogen protecting group, selected from the groupconsisting of tert-butyloxycarbonyl (Boc), toluenesulfonyl (Tosyl), andtrifluoromethanesulfonyl. Preferably, the nitrogen protecting group P₃is tert-butyloxycarbonyl (Boc).

The intermediate compound of formula (C12), as described in Scheme 13above, can be prepared according to the method disclosed in WO2014/143638 (example 2).

The reaction as outlined in Scheme 13 can be performed in the presenceof a Grignard reagent, or with a Lewis acid. The Grignard reagent usedto perform the reaction, as outlined in Scheme 13, can be selected fromthe group consisting of MeMgBr, MeMgCl, MeMgI, EtMgBr, EtMgCl, EtMgI,iPrMgCl, iPrMgBr, iPrMgI, or mixtures thereof. Preferably, the Grignardreagent is selected from MeMgBr and MeMgCl. The Lewis acid that can beused to perform the reaction, as outlined in Scheme 13, can be selectedfrom the group consisting of MgCl₂, MgBr₂, MgI₂ or mixtures thereof.

Optionally, the reaction, as described in Scheme 13, can be performed inthe presence of a base. The base can be any suitable base that a skilledperson would select based on a general textbook. The base can be forexample, but not limited to, selected from, triethylamine,N,N-diisopropylethylamine (DIPEA), 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU), 1,4-diazabicyclo[2.2.2] octane (DABCO), or mixtures thereof.Preferably, the base is triethylamine, DBU, or mixtures thereof.

The aldehyde source used to perform the reaction can be selected fromthe group consisting of formaldehyde, paraformaldehyde, urotropine, and2,4,6-trimethyl-1,3,5-trioxane. Preferably, the aldehyde source isparaformaldehyde.

Suitable solvents that can be used for the reaction are, for example,but not limited to, 1,4-dioxane, tetrahydrofuran (THF), 2-methyltetrahydrofuran, diethyl ether, or mixtures thereof.

The synthesis of compound of formula (C13) is advantageously performedwhen the Grignard reagent is MeMgBr, the aldehyde source isparaformaldehyde, and the oxygen protecting group P₂ istert-butyloxycarbonyl. In another embodiment, the synthesis of compoundof formula (C13) is also advantageously performed when the Lewis acid isMgCl₂, the aldehyde source is paraformaldehyde, and the oxygenprotecting group P₂ is tert-butyloxycarbonyl. The reaction is bestperformed at a temperature between room temperature to reflux. Thetemperature may need to be higher than room temperature in order to getgood yields. Particularly, when using a reactive Grignard reagent thetemperature may need to be between −30° C. to reflux. The refluxtemperature is preferably at about 60° C. to about 80° C., mostpreferably at about 65° C. to about 75° C. Performing the reaction underthose conditions is particularly advantageous as the reaction provides100% regioselectivity, thus making the present step especially suitablefor a large-scale manufacture.

In one embodiment, the compound of formula (I), or a pharmaceuticallyacceptable salt thereof, can be prepared by a process comprising thesteps of reacting a compound of formula (C12) with a Grignard reagent inthe presence of an aldehyde source, to obtain a compound of formula(C13), as outlined in Scheme 13, and further reacting the compound offormula (C13) to obtain a compound of formula (I), or a salt thereof.

3.2. Compound of Formula (C13)

In another embodiment, the invention provides a useful intermediate forthe synthesis of a compound of formula (III), or a salt thereof, acompound of formula (C13),

wherein P₃ is a nitrogen protecting group, as defined above in Section3.1.

In another embodiment, the present invention provides for the use of acompound of formula (C13) for preparing a compound of formula (III), ora salt thereof.

In another embodiment, the present invention provides for the use of acompound of formula (C13) for preparing a compound of formula (I), or apharmaceutically acceptable salt thereof.

3.3. Synthesis of Compound of Formula (III), or a Salt Thereof

In another embodiment, the present invention provides a process forpreparing a compound of formula (III), or a salt thereof, the processcomprising reacting the compound of formula (C13) with an inorganicbase, in the presence of a methylating agent, to obtain a compound offormula (III), or a salt thereof, as outlined below in Scheme 14.

wherein P₃ a nitrogen protecting group, as defined above in Section 3.1.

The inorganic base used to perform the reaction are inorganic bases fromwhich salts can be derived include, for example, ammonium salts andmetals from columns I to XII of the periodic table. In certainembodiments, the salts are derived from sodium, potassium, ammonium,calcium, magnesium, iron, silver, zinc, and copper; particularlysuitable salts include ammonium, potassium, sodium, calcium andmagnesium salts. Preferably, the inorganic base is an alkali metal base.Examples of suitable bases are, for example, Na₂CO₃, K₂CO₃, Cs₂CO₃, ormixtures thereof. Preferably, the base is potassium carbonate (K₂CO₃).

The methylating agent that can be used to transform the alcohol into amethoxy group can be any methylating agent the skilled person wouldselect based on general textbooks. Examples for suitable methylatingagents are methyl iodide, methyl bromide, methyl chloride,dimethylsulfate, methyl triflate (MeOTf), 4-methylsulfonyltoluene,methyl benzenesulfonate and mixtures thereof. Preferably, methyl iodide,methyl benzenesulfonate, and dimethyl sulfate. Preferably, themethylating agent is dimethyl sulfate.

Suitable solvent that can be used for the reaction are, for example,dimethylformamide (DMF), dimethoxyethane (DME), tetrahydrofuran (THF),dimethyl sulfoxide (DMSO), toluene, acetonitrile or mixtures thereof.Preferably, the solvent is dimethylformamide (DMF).

The synthesis of compound of formula (III), or a salt thereof, asdescribed in Scheme 14, is advantageously performed when the methylatingagent is dimethyl sulfate, and the base is an alkali base such aspotassium carbonate. In particular, the reaction performs well at atemperature of about 15° C. to about 35° C. Preferably, from about 20°C. to about 25° C.

In one embodiment, the compound of formula (I), or a pharmaceuticallyacceptable salt thereof, can be prepared by the process comprising thesteps of preparing a compound of formula (III), or a salt thereof, byreacting a compound of formula (C13) with a base in the presence of analkylating agent, as outlined in Scheme 14.

In another embodiment, the present invention provides a process forpreparing a compound of formula (III), or a salt thereof, as disclosedherein, the process comprising the steps of:

-   (i) preparing the compound of formula (C13), as described in Section    3.1; and-   (ii) further reacting the compound of formula (C13), as described in    Section 3.3;    to obtain the compound of formula (III), or a salt thereof.

4. Synthesis of a Compound of Formula (I)=(II)+(III): 4.1. Synthesis ofa Compound of Formula (C15)

In one embodiment, the process for preparing a compound of formula (I),or a pharmaceutically acceptable salt thereof, comprises reacting acompound of formula (II), or a salt thereof, with a compound of formula(III), or a salt thereof, in the presence of an Iridium catalyst in asolvent, under a hydrogen pressure, optionally in the presence of anadditive, to obtain a compound of formula (C15), or salt thereof, asdescribed in Scheme 15 vide infra,

In another embodiment, the present invention provides a process forpreparing a compound of formula (C15), or a salt thereof, said processcomprising the step of reacting a compound of formula (II), or a saltthereof, with a compound of formula (III), or a salt thereof, in thepresence of an Iridium catalyst, under hydrogen pressure, optionally inthe presence of an additive, to provide the compound of formula (C15),or a salt thereof, as outlined in Scheme 15 below.

wherein P₃ is a nitrogen protecting group, as defined above in Section3.1; andwherein R is a C₁-C₆alkyl, preferably R is methyl.

The catalyst used to perform the reaction can be, for example, selectedfrom the group consisting of [Ru(Triphos)(CO)H₂],[Ru(S)-BINAP(p-cymene)Cl]Cl, [Ru(CO)ClH(PPh₃)₃], [Ru(R)-BINAP(benzene)Cl]Cl, Ir(CO)₂acac, Ir(COD)Cl, Ir(CO)₃, and IrCl₃,xH₂O.Preferably, the catalyst is an Iridium catalyst selected from the groupconsisting of Ir(CO)₂acac, Ir(COD)Cl, Ir(CO)₃, and IrCl₃,xH₂O. Thecatalyst can be present in a range from about 0.05 mol % to about 10.0mol %. Preferably, the catalyst is present in a range from 0.1 mol % toabout 5.0 mol %. Suitable solvents used for the reaction are, forexample, methanol, ethanol, isopropanol, ethylene glycol, diethylcarbonate, DMSO, acetonitrile, tetrahydrofuran, or mixtures thereof.

The additive can be a ligand, a base, an acid, or mixtures thereof. Theadditive can be selected from, for example, but not limited to, thegroup consisting of tetrabutylammonium iodide (TBAI),((oxydi-2,1-phenylene)bis(diphenylphosphine)) (DPEPhos), triethylamine(Et₃N), sodium trifluoromethanesulfonate (NaOTf),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos),1,4-Diazabicyclo[2.2.2] octane (DABCO), tris(4-fluorophenyl)phosphine((4-F—C₆H₄)₃P), acetic acid, N-bromosuccinimide (NBS),N-chlorosuccinimide (NCS), or mixtures thereof.

The reaction as described in Scheme 15 is performed particularly wellwhen 0.1 mol % of Ir(CO)₂acac catalyst is present, in ethanol assolvent, under hydrogen pressure. In particular, the reaction performswell at a temperature in a range from about room temperature to reflux.Preferably, the temperature is in a range from about 60° C. to about100° C. Typically, the temperature is about 80° C. The reaction is bestperformed in the presence of hydrogen. The pressure of hydrogen in thereaction can be in a range from about 1 bar to about 30 bar, preferablybetween about 2.5 bar to about 20 bar. Performing the reaction underthose conditions is particularly advantageous as the reaction is highlyefficient and the amount of by-product formation is reduced compared tothe preparation of compound of formula (C15) described in WO 2015/009616(Intermediate 4-3, on page 127-128).

In another embodiment, the present invention provides a process forpreparing a compound of formula (C15), or a salt thereof, the processcomprising the step of reacting a compound of formula (II), or a saltthereof, with a compound of formula (III), or a salt thereof, asdescribed in Scheme 15, to prepare a compound of formula (C15), or asalt thereof, wherein the aldehyde group on the compound of formula(III), or salt thereof, is first reduced to the corresponding alcohol toobtain an intermediate compound of formula (IIIa), or a salt thereof,

wherein P₃ is a nitrogen protecting group, as defined above in Section3.1; andwherein R is a C₁-C₆alkyl, preferably R is methyl.

The compound of formula (IIIa), or a salt thereof, is then reacted witha compound of formula (II), or salt thereof, in the presence of anIridium catalyst in a solvent, in a hydrogen atmosphere, optionally inthe presence of an additive, as described above in Section 4.1.

In another embodiment, the present invention provides for an in situreduction of the aldehyde group on compound of formula (III), or a saltthereof, to the corresponding alcohol to obtain a compound of formula(IIIa), or a salt thereof. The compound of formula (IIIa), or a saltthereof, is then reacted with a compound of formula (II), or a saltthereof, in the presence of an Iridium catalyst in a solvent, underhydrogen pressure, optionally in the presence of an additive, asdescribed above in Section 4.1.

4.2. Compound of Formula (I), or a Pharmaceutically Acceptable SaltThereof

In another embodiment, the present invention provides a process asdefined in Section 4.1, wherein the compound of formula (C15), or a saltthereof is further reacted under hydrolyzing conditions to obtain acompound of formula (I), or a pharmaceutically acceptable salt thereof.

The term “hydrolyzing conditions” refers to the hydrolysis of an estergroup of formula —CO₂R, wherein R is C₁-C₆alkyl, such as methyl, to forma carboxylic acid of formula —CO₂H. The ester group can be hydrolyzed,for example, under basic conditions (e.g. using an alkali metal basesuch as NaOH, LiOH or KOH), or under acidic conditions (eg. usingmineral acids, such as HCl, H₂SO₄, HBr, H₃PO₄) to provide a carboxylicacid.

In one embodiment, the compound of formula (C15), or a salt thereof, isreacted under hydrolyzing conditions to obtain the correspondingcarboxylic acid, as outlined in Scheme 1. For example, using thehydrolyzing conditions as described in WO2015/009616 (example 26, onpage 174).

Certain variants, or alternative processes, to prepare a compound offormula (I), or a pharmaceutically acceptable salt thereof, aredescribed herein below. For example, the process comprises the followingsteps:

-   (i) preparing a compound of formula (S)-(C4), as disclosed in    Section 1.1,-   (ii) preparing a compound of formula (S)-(C5), by reacting a    compound of formula (S)-(C4); under reductive enzymatic conditions,    as disclosed in Section 1.2;-   (iii) preparing a compound of formula (C13), as disclosed in Section    3.2;-   (iv) preparing a compound of formula (III), or a salt thereof, as    disclosed in Section 3.3;-   (v) reacting the compound of formula (II), or a salt thereof, with a    compound of formula (III), or a salt thereof, to obtain a compound    of formula (C15), or a salt thereof, as disclosed in Section 4.1;    and-   (vi) reacting the compound of formula (C15), or a salt thereof,    under hydrolyzing conditions to obtain a compound of formula (I), or    a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention also provides a process forpreparing a compound of formula (I), or a pharmaceutically acceptablesalt thereof, as described herein below. For example, the processcomprises the following steps:

-   (i) preparing a compound of formula (S)-(C5), by reacting a compound    of formula (S)-(C4), under reductive enzymatic conditions, as    disclosed in Section 1.2;-   (ii) preparing a compound of formula (C13) as disclosed in Section    3.2; and-   (iii) reacting the compound of formula (II), or a salt thereof, with    a compound of formula (III), or a salt thereof, as disclosed in    Section 4.1.

In another embodiment, the present invention also provides a process forpreparing a compound of formula (I), or a pharmaceutically acceptablesalt thereof, the process comprising the following steps:

-   (i) preparing a compound of formula (C5), by reacting a compound of    formula (C4), using an enzymatic catalyzed step, as disclosed in    Section 2.2;-   (ii) preparing a compound of formula (C13) as disclosed in Section    3.2;-   (iii) preparing a compound of formula (III), or a salt thereof, as    disclosed in Section 3.3;-   (iv) reacting the compound of formula (II) or a salt thereof with a    compound of formula (III), or a salt thereof, to obtain a compound    of formula (C15), or a salt thereof, as disclosed in Section 4.1;    and-   (v) reacting the compound of formula (C15), or a salt thereof, under    hydrolyzing conditions to obtain a compound of formula (I), or a    pharmaceutically acceptable salt thereof.

In another embodiment, the present invention also provides a process forpreparing a compound of formula (I), or a pharmaceutically acceptablesalt thereof, the process comprising the following steps:

-   (i) preparing a compound of formula (C5), by reacting a compound of    formula (C4), under reductive enzymatic conditions, as disclosed in    Section 2.2;-   (ii) preparing a compound of formula (C13) as disclosed in Section    3.2; and-   (iii) reacting the compound of formula (II) or a salt thereof with a    compound of formula (III), or a salt thereof, as disclosed in    Section 4.1.

In yet another embodiment, the present invention relates to a processfor preparing a pharmaceutical composition, the process comprising theprocess according to Section 4.2 and mixing the obtained compound offormula (I), or a pharmaceutically acceptable salt thereof, with apharmaceutically acceptable excipient.

The compound of formula (I), or a pharmaceutically acceptable saltthereof, prepared as described above may optionally be further purifiedby recrystallization from a suitable solvent and may optionally bemilled or sieved in order to obtain the final pharmaceutically activeingredient.

Once the pharmaceutically active ingredient, compound of formula (I), ora pharmaceutically acceptable salt thereof, is obtained (as describedabove) it can be mixed with a pharmaceutically acceptable excipient.This can be achieved by mixing, granulating, compacting and the like.This way, a pharmaceutical composition can be prepared and used for thepreparation of final dosage forms, such as tablets or capsules, or anyother suitable pharmaceutical composition.

Definitions

The term “catalyst” as used herein refers to a catalytic amount of achemical agent that enhances the rate of a chemical reaction by loweringthe activation energy for the chemical reaction. The catalyst can be aheterogeneous catalyst or a homogenous catalyst. The term “heterogeneouscatalyst” refers to a catalyst supported on a carrier, typicallyalthough not necessarily a substrate comprised of an inorganic material,for example, a porous material such as carbon, silicon and/or aluminumoxide. The term “homogeneous catalyst” refers to a catalyst that is notsupported on a carrier.

The term “one-pot” “or “one-pot process” means that in a series (i.e. ina succession) of reactions, for example two or more successivereactions, each reaction product is provided for the next reactionwithout isolation and purification. The one-pot processes defined hereinencompass not only a series (i.e. a succession) of reactions conductedin a single reaction vessel, but also a series (i.e. a succession) ofreactions conducted in a plurality of reaction vessels (e.g., bytransferring the reaction mixture from one vessel to other) withoutisolation and purification. Preferably, the one-pot process is conductedin a single reaction vessel.

The term “ligand” means any compound, achiral or chiral, that can form acomplex with a transition metal. The term “chiral” refers to moleculeswhich have the property of non-superimposability on their mirror imagepartner, while the term “achiral” refers to molecules which aresuperimposable on their mirror image partner.

The term “amount” herein refers either to the weight of the compounds orto the molar amount of the compounds.

The term “protecting group” may be present and should protect thefunctional groups concerned against unwanted secondary reactions, suchas acylations, etherifications, esterifications, oxidations, solvolysisand similar reactions. It is a characteristic of protecting groups thatthey lend themselves readily, i.e. without or with very limitedundesired secondary reactions, to removal, typically by solvolysis,reduction, photolysis or also by enzyme activity, for example underconditions analogous to physiological conditions, and that they are notpresent in the end-products. The specialist knows, or can easilyestablish, which protecting groups are suitable with the reactionsmentioned hereinabove and hereinafter. Preferably, if two or moreprotecting groups are present in one intermediate mentioned, they arechosen so that, if one of the groups needs to be removed, this can bedone selectively, e.g. using two or more different protecting groupsthat are cleavable under different conditions, e.g. one class by mildhydrolysis, the other by hydrolysis under harder conditions, one classby hydrolysis in the presence of an acid, the other by hydrolysis in thepresence of a base, or one class by reductive cleavage (e.g. bycatalytic hydrogenation), the other by hydrolysis, or the like. Suitablenitrogen protecting groups are conventionally used in peptide chemistryand are described e.g. in the relevant chapters of standard referenceworks such as J. F. W. McOmie, “Protective Groups in Organic Chemistry”,Plenum Press, London and New York 1973; T. W. Greene and P. G. M. Wuts,“Greene's Protective Groups in Organic Synthesis”, Fourth Edition,Wiley, New York 2007; in “The Peptides”; Volume 3, Academic Press,London and New York 1981, and in “Methoden der organischen Chemie”(Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15/I,Georg Thieme Verlag, Stuttgart 1974.

The term “oxygen protecting group” generally comprises any group whichis capable of reversibly protecting the oxygen functionality. A hydroxylprotecting group may, for example, be selected from a group comprising(especially consisting of) a silyl protecting group, especiallydiarylalkyl-silyl, such as diphenyl-tert-butylsilyl, or more preferablytri-alkylsilyl, such as tert-butyldimethylsilyl or trimethylsilyl; anacyl group, e.g. alkanoyl, such as acetyl; benzoyl; alkoxycarbonyl, suchas tert-butoxycarbonyl (Boc), or arylalkoxycarbonyl, such asbenzyloxycarbonyl; tetrahydropyranyl; unsubstituted or substitutedarylalkyl, such as benzyl or p-methoxybenzyl, and methoxymethyl.Exemplary hydroxyl protecting groups are acetyl, propionyl, butynyl,pivaloyl, 2-chloroacetyl, benzoyl; carbonate derivatives such asphenoxycarbonyl, t-butoxycarbonyl ethoxycarbonyl, vinyloxycarbonyl,2,2,2-trichloroethoxycarbonyl and benzyloxycarbonyl; alkyl ether forminggroups such as methyl, methoxymethyl, methylthiomethyl, benzyloxymethyl,t-butoxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl,2-(trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tetrahydrofuranyl,t-butyl, triphenylmethyl, benzyl, diphenylmethyl, allyl; silyl etherforming groups such as trialkylsilyl, trimethylsilyl, triethylsilyl,t-butyldimethylsilyl, t-butyldiphenylsilyl, isopropyldialkylsilyl,alkyldiisopropylsilyl, triisopropylsilyl, t-butyldialkyl-silyl; andcarbamates such as N-phenylcarbamate or N-imidazoylcarbamate. Inparticular, a hydroxyl protecting group is a silyl group according tothe formula SiR7R8R9, wherein R7, R8 and R9 are, independently of eachother, alkyl or aryl. Examples for R7, R8 and R9 are methyl, ethyl,isopropyl, t-butyl and phenyl. In particular, R7, R8 and R9 are ethyl ormethyl.

The term “nitrogen protecting group” generally comprise: C₁-C₆-alkyl,preferably C₁-C₄-alkyl, more preferably C₁-C₂-alkyl, (e.g. acetyl,allyl, tertbutyl) most preferably C₁-alkyl which is mono-, di- ortri-substituted by trialkylsilyl-C₁-C₇-alkoxy (eg. trimethylsilyethoxy),aryl, preferably phenyl, or an heterocyclic group (e.g., benzyl, cumyl,benzhydryl, pyrrolidinyl, trityl, pyrrolidinylmethyl,1-methyl-1,1-dimethylbenzyl, (phenyl)methylbenzene) wherein the arylring or the heterocyclic group is unsubstituted or substituted by one ormore, e.g. two or three, residues, e.g. selected from the groupconsisting of C₁-C₇-alkyl, hydroxy, C₁-C₇-alkoxy, C₂-C₈-alkanoyl-oxy,halogen, nitro, cyano, and CF₃; aryl-C₁-C₂-alkoxycarbonyl (preferablyphenyl-C₁-C₂-alkoxycarbonyl (eg. benzyloxycarbonyl (Cbz),benzyloxymethyl (BOM), pivaloyloxymethyl (POM)); alkenyloxycarbonyl;C₁-C₆alkylcarbonyl (eg. acetyl or pivaloyl); C₆-C₁₀-arylcarbonyl;C₁-C₆-alkoxycarbonyl (eg. tertbutoxycarbonyl (Boc), methylcarbonyl,trichloroethoxycarbonyl (Troc), pivaloyl (Piv), allyloxycarbonyl);C₆-C₁₀-arylC₁-C₆-alkoxycarbonyl (e.g. 9-fluorenylmethyloxy carbonyl(Fmoc)); allyl or cinnamyl; sulfonyl or sulfenyl; succinimidyl group,silyl groups (e.g. triarylsilyl, trialkylsilyl, triethylsilyl (TES),trimethylsilylethoxymethyl (SEM), trimethylsilyl (TMS),triisopropylsilyl or tertbutyldimethylsilyl).

As used herein, the term “C₁-C₁₂alkyl” refers to a straight or branchedhydrocarbon chain radical consisting solely of carbon and hydrogenatoms, containing no unsaturation, having from one to twelve carbonatoms, and which is attached to the rest of the molecule by a singlebond. The term “C₁-C₆alkyl” is to be construed accordingly. Examples ofC₁-C₁₂alkyl include, but are not limited to, ethyl, n-propyl,1-methylethyl (iso-propyl), n-butyl, n-pentyl 1,1-dimethylethyl(tert-butyl).

As used herein, the term “Halogen” or “Halo” refers to bromo, chloro,fluoro or iodo.

The term “about”, as used herein, is intended to provide flexibility toa numerical range endpoint, providing that a given value may be “alittle above” or “a little below” the endpoint accounting for variationsone might see in the measurements taken among different instruments,samples, and sample preparations. The term usually means within 10%,preferably within 5%, and more preferably within 1% of a given value orrange.

The term “room temperature” or “ambient temperature” as used herein,unless specified otherwise, means a temperature from 15 to 30° C., suchas from 20 to 30° C., particularly such as from 20 to 25° C. The term“internal temperature” as used herein, unless specified otherwise, meansthe temperature measured inside of the reactor vessel in which thereaction is performed. Such temperature is expressed in degree Celsius.The term “jacket temperature” as used herein, unless specifiedotherwise, means the temperature measured inside the jacket of thereactor vessel in which the reaction is performed.

The term “stereoisomers” means one of the absolute configurations of asingle organic molecule having at least one asymmetric carbon. Also, asused herein, the term refers to any of the various stereo isomericconfigurations which may exist for a given compound of the presentinvention and includes geometric isomers. It is understood that asubstituent may be attached at a chiral center of a carbon atom.Therefore, the invention includes enantiomers, diastereomers orracemates of the compound. “Enantiomers” are a pair of stereoisomersthat are non-superimposable mirror images of each other. A 1:1 mixtureof a pair of enantiomers is a “racemic” mixture. The term is used todesignate a racemic mixture where appropriate. “Diastereoisomers” arestereoisomers that have at least two asymmetric atoms, but which are notmirror-images of each other. The absolute stereochemistry is specifiedaccording to the Cahn-Ingold-Prelog R-S system. When a compound is apure enantiomer the stereochemistry at each chiral carbon may bespecified by either R or S. Resolved compounds whose absoluteconfiguration is unknown can be designated (+) or (−) depending on thedirection (dextro- or levorotatory) which they rotate plane polarizedlight at the wavelength of the sodium D line. Certain of the compoundsdescribed herein contain one or more asymmetric centers or axes and maythus give rise to enantiomers, diastereomers, and other stereoisomericforms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)-. The present invention is meant to include all such possibleisomers, including racemic mixtures, optically pure forms andintermediate mixtures.

In the formulae of the present application the term “

” on a C-sp³ indicates the absolute stereochemistry, either (R) or (S).

In the formulae of the present application the term “

” on a C-sp³ indicates the absolute stereochemistry, either (R) or (S).

The term “resolution” refers to the separation or concentration ordepletion of one of the stereoisomers of a molecule.

The term “seed” can be used as a noun to describe one or more crystalsof a crystalline compound of same formula as the final compound of thereaction of interest. The term “seed” can also be used as a verb todescribe the act of introducing said one or more crystals of a saidcrystalline compound into an environment (including, but not limited to,for example, a solution, a mixture, a suspension, or a dispersion)thereby resulting in the formation of more crystals of the finalcompound.

The term “pharmaceutically acceptable salts” or “salt thereof” refers tosalts that can be formed, for example, as acid addition salts,preferably with organic or inorganic acids. For isolation orpurification purposes it is also possible to use pharmaceuticallyunacceptable salts, for example picrates or perchlorates. Fortherapeutic use, only pharmaceutically acceptable salts or freecompounds are employed (where applicable in the form of pharmaceuticalpreparations), and these are therefore preferred. The salts of thecompound of formula (I), and intermediates, as described in the presentinvention, are preferably pharmaceutically acceptable salts; suitablecounter-ions forming pharmaceutically acceptable salts are known in thefield. The term “pharmaceutically acceptable” refers to those compounds,materials, compositions, and/or dosage forms which are suitable for usein contact with the tissues of human beings and animals withoutexcessive toxicity, irritation, allergic response, or other problem orcomplication, commensurate with a reasonable benefit/risk ratio.

The term “additive” as used herein refers to a base, an acid, a ligand,or any other chemical species that can enhanced the reactivity of thereaction.

As used in this specification and the appended claims, the singularforms “a”, “an”, and “the” include plural referents unless the contextclearly indicates otherwise.

Similarly, “comprise”, “comprises”, “comprising”, “include”, “includes”and “including” are interchangeable and not intended to be limiting.

Abbreviations

-   δ Chemical shift-   (4-F—C₆H₄)₃P tris(4-fluorophenyl)phosphine-   (Boc)₂O di-tert-butyl carbonate-   (R)-(+)-MeO-BIPHEP)    (R)-(+)-(6,6′-Dimethoxybiphenyl-2,2′-diyl)bis(diphenylphosphine)-   (R)-segphos    (R)-(+)-5,5′-Bis(diphenylphosphino)-4,4′-bi-1,3-benzodioxole-   (R,R)-Ph-BPE (+)-1,2-Bis((2R,5R)-2,5-diphenylphospholano)ethane-   (S)-BINAP (S)-(2,2′-bis(diphenylphosphino)-1,1′-binaphthyl)-   (S)-SDP    (S)-(−)-7,7′-Bis(diphenylphosphino)-2,2′,3,3′-tetrahydro-1,1′-spirobiindene-   (S)-Tol-BINAP (R)-(+)-2,2′-Bis(di-p-tolylphosphino)-1,1′-binaphthyl-   (S)-XylBINAP    1,1′-Binaphthalene-2,2′-diylbis[bis(3,5-dimethylphenyl)phosphine]-   (S,S)-Et-DUPHOS (+)-1,2-Bis[(2S,5S)-2,5-diethylphospholano]benzene-   (S,S)-iPr-DUPHOS    (+)-1,2-Bis[(2S,5S)-2,5-diisopropylphospholano]benzene-   (S,S)-Me-DUPHOS (+)-1,2-Bis[(2S,5S)-2,5-dimethylphospholano]benzene-   (S,S)-Me-Ferrocelane    1,1′-Bis[(2S,5S)-2,5-dimethylphospholano]ferrocene-   [Rh(COD)Cl]₂ Chloro(1,5-cyclooctadiene)rhodium(I) dimer-   [Rh(COD)OMe]₂ Methoxy(cyclooctadiene)rhodium(I) dimer-   [Rh(MeCN)₂(COD)]BF₄ Bis(1,5-cyclooctadiene)rhodium(I)    tetrafluoroborate-   [Rh(OH)((S)-BINAP)]₂ Hydroxy[-(S)-BINAP]-rhodium(I) Dimer-   [RhCl(S)-BINAP]₂ Chloro[(S)-BINAP]-rhodium(I) Dimer-   ¹H-NMR Proton nuclear magnetic resonance-   9-BBN 9-borabicyclo(3.3.1)nonyl-   acac acetylacetone-   alloc allyloxycarbonyl-   Boc/Boc₂O Tert-butyloxycarbonyl/di-tert-butyl dicarbonate-   Br/d/m/t/s/q Broad/doublet/multiplet/triplet/singlet/quadruplet-   Bz/Cbz Benzyl/Benzyl chloroformate-   CDCl₃ Chloroform-deuterated-   COD Cyclooctadiene-   CPME Cyclopentyl methyl ether-   DABCO 1,4-Diazabicyclo[2.2.2]octane-   DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene-   DEM diethoxymethane-   DIPEA N,N-Diisopropylethylamine-   DMA Dimethylacetamide-   DMAP 4-dimethylaminopyridine-   DMF dimethylformamide-   DMSO/DMSO-d6 Dimethyl sulfoxide/Dimethyl sulfoxide-deuterated-   DPEPhos oxydi-2,1-phenylene)bis(diphenylphosphine-   EDTA-4Na.2H₂O Tetrasodium dihydrate-   ee Enantiomeric excess-   eq equivalent-   Et₃N Triethylamine-   Et₃SiH Triethylsilane-   FAD Flavin adenine dinucleotide-   g/mg Gram(s)/milligram(s)-   GC Gas chromatography-   GDH Glucose dehydrogenase-   H₂ Dihydrogen-   HCl/HF Hydrogen Chloride/Hydrogen fluoride-   HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid-   HPLC High Performance Liquid Chromatography-   HRMS High resolution mass spectrometry-   Hz/MHz Hertz/Mega Hertz-   IT/JT Internal temperature in celsius/Jacket temperature in celsius-   J Coupling constant-   K₂CO₃ Potassium carbonate-   KRED Ketoreductase-   LCMS Liquid chromatography-mass spectrometry-   M Molar-   MCC Microcrystalline cellulose-   mL/L Milliliter(s)/Liter(s)-   Mol/mmol Mole(s)/Millimole(s)-   MOPS 3-(N-morpholino)propanesulfonic acid-   MTBE Methyl tert-butyl ether-   N normal-   Na₂HPO₄ Disodium phosphate-   NAD Nicotinamide adenine dinucleotide-   NADP Nicotinamide adenine dinucleotide phosphate-   NaHCO₃ Sodium bicarbonate-   NaOTf sodium trifluoromethanesulfonate-   nbd norbornadiene-   NBS/NCS N-bromosuccinimide/N-chlorosuccinimide-   NH₄Cl/NaCl Ammonium chloride/Sodium chloride-   NHC-Pd(II)N-heterocyclic carbene-palladium (II)-   PBS Phosphate buffer saline-   Pd(O₂CCF₃)₂ Palladium(II) trifluoroacetate-   Pd(OAc)₂ palladium(II) acetate-   Pd/C Palladium on carbon-   PIPES piperazine-N,N′-bis(2-ethanesulfonic acid-   ppm Parts per million-   PTS tocopherol polyethylene glycol succinates-   Rh(acac)(C₂H₄)₂ Acetylacetonatobis(ethylene)rhodium(I)-   Rh(acac)(COD) (Acetylacetonato)(1,5-cyclooctadiene)rhodium(I)-   Rh(COD)BF₄ Bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate-   Rh(nbd)₂BF₄ Bis(norbornadiene)rhodium(I) tetrafluoroborate-   RPM Rotations per minute-   TBAI tetrabutylammonium iodide-   TBDPS tert-butyldiphenylsilyl-   TBS Tert-butyldimethylsilyl-   TES/TESOTf Triethylsilyl trifluoromethanesulfonate/triethylsilyl-   TFA Trifluoroacetic acid-   THF tetrahydrofuran-   TIPS triisopropylsilyl-   TMS trimethylsilyl-   Tosyl Toluenesulfonyl-   TPGS Tocopherol polyethylene glycol succinates-   TRIS 2-Amino-2-(hydroxymethyl)propane-1,3-diol-   v/v volume to volume-   Wt % Weight percent-   Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene-   XRPD X-ray diffraction pattern

EXAMPLES

The following examples are merely illustrative of the present inventionand they should not be considered as limiting the scope of the inventionin any way, as these examples, and other equivalents thereof will becomeapparent to those skilled in the art in the light of the presentinvention, and the accompanying claims.

Syntheses

The skilled person will appreciate that the general synthetic routesdetailed above show common reactions to transform the starting materialsas required. When specific reactions are not provided the skilled personwill know that such reactions are well known to those skilled in the artand appropriate conditions considered to be within the skilled person'scommon general knowledge. The starting materials are either commerciallyavailable compounds or are known compounds and can be prepared fromprocedures described in the organic chemistry art.

Compounds as described herein, in free form, may be converted into saltform and vice versa, in a conventional manner understood by thoseskilled in the art. The compounds in free or salt form can be obtainedin the form of hydrates or solvates containing a solvent used forcrystallization. Compounds described herein can be recovered fromreaction mixtures and purified in a conventional manner. Isomers, suchas stereoisomers, may be obtained in a conventional manner, e.g. byfractional crystallization or asymmetric synthesis from correspondinglyasymmetrically substituted, e.g. optically active, starting materials.The various starting materials, intermediates, and compounds of thepreferred embodiments may be isolated and purified, where appropriate,using conventional techniques such as precipitation, filtration,crystallization, evaporation, distillation, and chromatography. Unlessotherwise stated. Salts may be prepared from compounds by knownsalt-forming procedures.

The compounds described herein can be prepared, e.g. using the reactionsand techniques described below and in the examples. The reactions may beperformed in a solvent appropriate to the reagents and materialsemployed and suitable for the transformations being effected. It will beunderstood by those skilled in the art of organic synthesis that thefunctionality present on the molecule should be consistent with thetransformations proposed. This will sometimes require a judgment tomodify the order of the synthetic steps or to select one particularprocess scheme over another in order to obtain a desired compound of theinvention.

It would be understood by the skilled person in the art, that thereactions were run on a small scale first in order to access if thestarting materials could react in high yields and high purities beforeto be scalable. The desired compounds obtained during such small scalereaction, that spontaneously crystallized, were used to enhance thelatest reactions, using the technique of “seeding”. Here belowapproximately 1% by weight or less of seeding crystals were added, ifneeded, to the reaction mixture to generate quicker the spontaneouscrystallization of the desired product.

Measurements Methods

Proton-NMR: measurements were performed on Bruker 400 Mhz spectrometer.Chemical shifts (δ-values) are reported in ppm downfield and the spectrasplitting pattern are designated as singlet (s), doublet (d), triplet(t), quartet (q), quintet (quint), multiplet, unresolved or overlappingsignals (m), broad signal (br). Deuterated solvents are given inparentheses.

HPLC: measurements were performed on Agilent 1200 HPLC with highpressure mixing (Column: Waters XBridge BEH C18) and Agilent 1290 UHPLC(Column: Water Acquity BEH C18)

1. C4 CPD method: Agilent 1200 HPLC with high pressure mixing

Solvents: Mobile phase A: 10 mM ammonium acetate in water and Mobilephase B: acetonitrile. This method was used only for compound of formula(C4).

2. 1601 method: Agilent 1290 UHPLC

Solvents: Mobile phase A: 0.05% TFA in water/acetonitrile 95/5 (v/v) andMobile phase B: 0.05% TFA in water/ACN 5/95 (v/v)

HRMS: Waters ACQUITY UPLC/SYNAPT HDMS QTOF system.

LCMS: Waters ACQUITY UPLC/SYNAPT HDMS QTOF system or Agilent 1290Infinity/MSD LC/MS system.

XRPD: measurements were performed on Bruker D2 phaser-source CuKαλ=1.5418 Å. One of ordinary skill in the art will appreciate that anX-ray diffraction pattern may be obtained with a measurement error thatis dependent upon the measurement conditions employed. In particular, itis generally known that intensities in a X-ray diffraction pattern mayfluctuate depending upon measurement conditions employed. It should befurther understood that relative intensities may also vary dependingupon experimental conditions and, accordingly, the exact order ofintensity should not be taken into account. Additionally, a measurementerror of diffraction angle for a conventional X-ray diffraction patternis typically about 5% or less, and such degree of measurement errorshould be taken into account as pertaining to the aforementioneddiffraction angles. Consequently, it is to be understood that thecrystal forms of the instant invention are not limited to the crystalforms that provide X-ray diffraction patterns completely identical tothe X-ray diffraction patterns depicted in the accompanying Figuresdisclosed herein. Any crystal forms that provide X-ray diffractionpatterns substantially identical to those disclosed in the accompanyingFigures fall within the scope of the present invention. The ability toascertain substantial identities of X-ray diffraction patterns is withinthe purview of one of ordinary skill in the art.

Example 1: Synthesis ofBenzyl-2-[4-(methoxycarbonyl)phenyl]-4-oxopiperidine-1-carboxylate (C4)According to the Following Sequence

Step 1: Synthesis ofBenzyl-2-[4-(methoxycarbonyl)phenyl]-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate (C3, Wherein P₁=Cbz and R=Methyl)

iPrMgCl (2N THF, 109.96 g, 54.98 mL, 2.0 eq) was charged in a reactor. Asolution of bis[2-(N,N-dimethylaminoethyl)] ether (2.5 eq, 22.03 g,137.46 mmol) in THF (24 mL) was added at 15-25° C. The mixture wasstirred for 1 hour. A solution of C1 (20.17 g, 76.98 mmol, 1.4 eq) inTHF (102 mL) was added slowly at 15-25° C. The mixture was heated to25-30° C., stirred for more than 1 hour, and checked by HPLC. Themixture was cooled to −30° C. A solution of C2 (methyl 4-iodobenzoate,6.0 g, 54.98 mmol, 1.0 eq) in THF (20 mL) was added, followed by asolution of benzyl chloroformate (1.15 eq, 10.79 g, 63.23 mmol) in THF(36 mL). The mixture was stirred for 2 hours and quenched with AcOH(6.60 g, 109.96 mmol, 2 eq). Isopropyl acetate (60 mL) was added.Hydrogen chloride (15%, 90 g) was added to adjust the pH=1-2. Theorganic layer was separated and washed with brine (15%, 100 g), andconcentrated. Isopropyl acetate (160 mL) was added and concentrated toremove the THF. The crude product was recrystallized in Isopropylacetate (114 mL) and n-heptane (120 mL). The product was dried at 60° C.to provide C3 as light yellow solid (16.0 g, 79.65% yield). ¹H-NMR (400MHz, DMSO-d6) δ (ppm)=8.11 (dd, J=8.39, 1.01 Hz, 1H), 7.91 (d, J=8.39Hz, 2H), 7.33-7.37 (m, 6H), 5.82 (d, J=7.20 Hz, 1H), 5.20-5.35 (m, 3H),3.83 (s, 3H), 3.41 (br. s, 1H), 3.31 (dd, J=16.64, 7.52 Hz, 1H), 2.66(br. d, J=16.55 Hz, 1H).

Step 2: Synthesis ofBenzyl-2-[4-(methoxycarbonyl)phenyl]-4-oxopiperidine-1-carboxylate (C4,Wherein P₁=Cbz and R=Methyl)

A solution of C3 (25 g, 68.42 mmol, 1.0 eq) in AcOH (200 mL) was heatedto 50-60° C. to form a clear solution. The solution was then cooled to35° C. Zn powder (13.42 g, 205.26 mmol, 3.0 eq) was added portionwisewhile keeping the inner temperature at 35-40° C. After addition, themixture was stirred for more than 8 hours and checked by HPLC. THF (250mL) was added. The mixture was cooled to 25° C., filtered, and thefilter cake was washed with THF (125 volume). The filtrate wasconcentrated to dryness. Isopropanol (375 mL) was added. The solutionwas cooled to 0-5° C. EDTA-4Na.2H₂O (40 g) in water (200 mL) was added.The mixture was neutralized to pH=9-10 with 30% sodium hydroxidesolution and stirred for 2 hours. The organic layer was collected,washed with brine (15%, 250 g) and concentrated to about 50 mL. MTBE(100 mL) was added and concentrated to about 50 mL. MTBE (80 mL) wasadded followed by n-heptane (20 mL) dropwise. Then the mixture wascooled to 0° C. gradually. The mixture was filtered and the filter cakewas dried to afford C4 as a light yellow solid (20.11 g, 80.0% yield).¹H NMR (400 MHz, CDCl₃) δ (ppm)=7.99 (d, J=8.31 Hz, 2H), 7.27-7.39 (m,7H), 5.83 (br. s, 1H), 5.14-5.28 (m, 2H), 4.20-4.42 (m, 1H), 3.92 (s,3H), 3.12-3.33 (m, 1H), 2.84-3.04 (m, 2H), 2.46-2.65 (m, 1H), 2.23-2.45(m, 1H).

Example 2: Synthesis of Benzyl(4S)-4-hydroxy-2-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate(C5, Wherein P₁=Cbz and R=Methyl)

A 0.1 M pH=7.0 PBS was prepared with disodium phosphate dodecahydrate(22.2 g), sodium dihydrogen phosphate dihydrate (6.2 g) and purifiedwater (999 g). To a reactor equipped with a pH meter 0.1 M pH=7.0 PBS(499 g), D-glucose (40.2 g, 233.14 mmol, 2.0 eq), NADP (EnzymeWorks,0.72 g), GDH (EnzymeWorks, 0.41 g) and KRED-EW124 (EnzymeWorks, 2.05 g)were added, followed by addition of emulsion of C4 (41 g, 111.60 mmol,1.0 eq) in DMSO (102.5 mL). The mixture was heated to JT≤45° C., IT41±3° C. and stirred at IT 41±3° C. for ≥16 h while controlling pH6.9-7.2 by adding 1M sodium hydroxide solution. A mixture of NADP (0.29g), GDH (0.16 g) and KRED-EW124 (0.82 g, #Enzyme Works Inc. China) in0.1 M pH=7.0 PBS (11 g) were charged and stirred at IT 41±3° C. for ≥20hours. The reaction was monitored by HPLC. The reaction was filtered toafford white wet cake. To a 1.0 L Radleys reactor equipped with anchoragitator crude C5 wet cake (80 g) and acetonitrile (500 mL) werecharged. The mixture was stirred to form a light yellow suspension (700RPM). The suspension was heated to IT=70±5° C. and stirred for 4 hours,and then cooled to IT=25±5° C. The suspension was filtered and the cakewas washed with acetonitrile (75 mL). To a clean 500 mL Radleys reactorequipped with anchor agitator the resulting mother liquor was charged.The mother liquid was concentrated to about 95 g, solvent exchanged withthree portions of toluene (105 g) to 95 g residue. Toluene (170 g) wascharged and the reaction was checked by GC(acetonitrile/(toluene+acetonitrile)≤1.2%). The suspension was heated toIT=80±5° C., held for 1 hour, cooled to IT=45±3° C. and adjusted theagitation speed to low mode. Sequential operations of seeding and agingfor 2 hours, charging n-heptane (10.2 g) in 0.5 hours and aging for 1hour, charging n-heptane (34 g) over 1.5 hours and aging for 0.5 hourswere carried out. The mixture was cooled to IT=10±3° C. over 7 hours andmaintained at 10±3° C. for 2 hours. The mixture was filtered and thecake was washed with cold mixed solvents of toluene (50 mL) andn-heptane (10 mL) to afford a light yellow solution of C5 (330 g,trans/cis=90/10, assay 6.8%, yield 52%). The mother liquor wastelescoped to the next step. ¹H-NMR (400 MHz, CDCl₃, mixture of twoisomers, data for the minor isomer is shown in brackets): δ (ppm)=7.99(d, J=8.44 Hz, 2H) [7.92 (d, J=8.44 Hz, 0.04H)], 7.23-7.39 (m, 7H)[7.10-7.18 (m, 0.21H)], 5.69 (br. s, 1H) [5.40-5.42 (m, 0.11H)], 5.19(s, 2H) [5.14 (s, 0.23H)], 4.26 (br. d, J=13.33 Hz, 1H) [4.18-4.20 (m,0.13H)], 3.91 (s, 3H) [3.90 (s, 0.4H)], 3.67-3.79 (m, 1H) [3.38-3.45 (m,0.11H)], 2.83 (td, J=13.51, 2.81 Hz, 1H), 2.64 (br. d, J=13.33 Hz, 1H)[2.41-2.47 (m, 0.12H)], 1.81-1.91 (m, 2H) [2.17-2.22 (m, 0.12H)],1.72-1.77 (m, 1H), 1.45-1.56 (m, 1H). HRMS: Calcd for C₂₁H₂₄NO₅ (M+H):370.1654m, found 370.1662.

Example 3: Synthesis of Methyl4-[(2S,4S)-4-ethoxypiperidin-2-yl]benzoate (Compound of Formula (II))According to the Following Sequence

Step 1: Synthesis of Benzyl(4S)-4-((tert-butyldimethylsilyl)oxy)-2-(4-(methoxycarbonyl)Phenyl)piperidine-1-carboxylate (C8, Wherein P₁=Cbz, P₂=TBS andR=Methyl)

To a 500 mL Radleys Reactor charged with C5 in a toluene/heptanesolution (1.0 eq, 145.67 g from previous step, assay 6.07%, 23.94 mmol).The solution was concentrated to about 25 g. Then dichloromethane (117.1g) was charged and the solution was cooled to 23±4° C. To the clearsolution, imidazole (3.42 g, 50.26 mmol, 2.1 eq) and TBS-Cl (6.13 g,40.69 mmol, 1.7 eq) were introduced. The yellow suspension was stirredat 23±4° C. for 10 hours. The reaction was monitored by HPLC. Then 10%Na₂CO₃ (70.7 g) was charged and the mixture was stirred for 1 hours. Theorganic phase was washed with 5% brine (53 g) and concentrated to about30 g. Then the solvent was exchange with toluene (45 g) to about 25 g.The residue was diluted with dichloromethane (66 g) and the mixture wasfiltered through a pad of 200-300 mesh silica gel (1.66 g). The silicagel was eluted with another portion of dichloromethane (17.5 g). Theeluent was concentrated and the residue was subjected to solventexchange with acetonitrile (71.1 g+98.2 g) to 90 g (yield 100%). C8 inacetonitrile solution was used in the next step. ¹H-NMR (400 MHz, CDCl₃,mixture of two isomers, data for the minor isomer is shown in brackets):δ (ppm)=8.01 (d, J=8.44 Hz, 2H) [7.94 (d, J=8.44 Hz, 0.17H)], 7.26-7.34(m, 7H) [7.09-7.18 (m, 0.13H)], 5.65 (br. d, J=2.04 Hz, 1H) [5.41 (br.d, J=2.04 Hz, 0.08H)], 5.19 (s, 2H) [5.13 (s, 0.16H)], 4.22 (br. d,J=13.69 Hz, 1H) [4.10-4.14 (m, 0.19H)], 3.92 (s, 3H) [3.90 (s, 0.3H)],3.62-3.69 (m, 1H) [3.43-3.50 (m, 0.08H)], 2.81 (td, J=13.54, 2.87 Hz,1H), 2.49 (br. d, J=13.57 Hz, 1H) [2.31-2.35 (m, 0.10H)], 1.84-1.92 (m,1H) [2.08-2.14 (m, 0.07H)], 1.74-1.75 (m, 1H), 1.48-1.59 (m, 1H), 0.86(s, 9H) [0.56 (s, 0.65H)], 0.03 (s, 3H) [0.09 (s, 0.27H)].

Step 2: Synthesis of Benzyl(4S)-4-ethoxy-2-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate (C9,Wherein P₁=Cbz, R=Methyl)

To a 250 mL Radleys Reactor equipped with impeller agitator C8 inacetonitrile solution (135.5 g, assay 12.53%, 35.10 mmol) was chargedand rinsed with acetonitrile (with 8.5 g). Et₃SiH (12.25 g, 105.31 mmol,3.0 eq) was charged. The reactor was cooled to IT=4±5° C. TESOTf (1.392g, 5.265 mmol, 0.15 eq) was charged. A solution of2,4,6-trimethyl-1,3,5-trioxane (4.64 g, 35.10 mmol, 1.0 eq) inacetonitrile (7.9 g) was added to the mixture in 60 min at IT=4±5° C.After addition, the mixture was stirred for 15 min and followed by HPLC.To the reaction mixture was charged 5% aqueous Na₂CO₃ (21.22 g) andwater (30 g). Followed by n-heptane (20.4 g) and the mixture was stirredat 25±5° C. for 30 min. Phase cut and the bottom acetonitrile phase wascollected. The acetonitrile phase was concentrated to about 65 g. MTBE(100.6 g) and 5% aqueous Na₂CO₃ (43.44 g) were charged to the residualacetonitrile solution. The mixture was stirred for 30 min. The upperMTBE phase was collected and filtered via Charcoal film. The charcoalfilm was washed with MTBE (7.4 g). The mother liquor was concentrated toabout 35 g. To the residue methanol (79.2 g) was charged and thesolution was concentrated to 70 g. The solution was telescoped to thenext step. ¹H NMR (400 MHz, CDCl₃, mixture of two isomers, data for theminor isomer is shown in brackets) δ (ppm)=8.01 (d, J=8.31 Hz, 2H) [7.96(d, J=8.31 Hz, 0.21H)], 7.29-7.32 (m, 7H) [7.07-7.22 (m, 0.40H)], 5.68(br. s, 1H) [5.32-5.34 (m, 0.10H)], 5.19 (s, 2H) [5.11 (s, 0.19H)], 4.27(br. d, J=13.08 Hz, 1H) [4.05-4.14 (m, 0.15H)], 3.91 (s, 3H) [3.89 (s,0.15H)], 3.41-3.54 (m, 2H) [3.14-3.25 (m, 0.21)], 3.30-3.40 (m, 1H)[3.86-3.75 (m, 0.13H)], 2.84 (td, J=13.51, 2.81 Hz, 1H), 2.66 (br. d,J=13.20 Hz, 1H), 1.62-1.95 (m, 2H), 1.40-1.53 (m, 1H), 1.18 (t, J=6.97Hz, 3H).

Step3: Synthesis of Methyl 4-((4S)-4-ethoxypiperidin-2-yl)benzoate(Removal of the Protecting Group P₁=Cbz-R=Methyl)

To a 500 mL autoclave charged with 10% Pd/C (50% wet, 3.83 g), C9solution in methanol (assay 19.97%, 192 g, 96.46 mmol) and methanol (28g). The reactor was purged with vacuum/H₂, three times. The mixture washydrogenated at 3 bar and at a temperature of 25±4° C. for 4 hours. Themixture was filtered and the Pd/C cake was washed with methanol (20 g).The mother liquor was concentrated to 48 g, solvent swapped twice with142 g isopropyl acetate to 106 g, cooled to 8±5° C., and 3% hydrogenchloride solution (90.2 g) was added. After phase separation, theaqueous phase was collected and washed with isopropyl acetate (86.4 g).To the aqueous phase MTBE (72 g) and 10% Na₂CO₃ (99.2 g) were added.After phase separation, the aqueous phase was extracted with MTBE (72g). The combined MTBE phase was washed with water (40 g). The MTBEsolution was introduced into the next step. ¹H NMR (400 MHz, CDCl₃,mixture of two isomers, data for the minor isomer is shown in brackets)δ (ppm)=7.96 (m, J=8.31 Hz, 2H), 7.40-7.46 (m, 2H), 4.06 (dd, J=11.62,2.45 Hz, 1H), 3.88 (s, 3H), 3.70-3.79 (m, 1H) [3.64-3.69 (m, 0.12H)],3.48-3.56 (m, 2H) [3.38-3.45 (m, 0.11H)], 3.11-3.18 (m, 1H) [3.21-3.26(m, 0.11H)], 2.88-2.97 (m, 1H) [2.73-2.80 (m, 0.12H)], 1.94-2.00 (m, 1H)[2.14-2.19 (m, 0.10H)], 1.84-1.89 (m, 1H) [2.02-2.07 (m, 0.12H)], 1.75(S, 1H), 1.65-1.70 (m, 1H) [1.45-1.49 (m, 0.10H)], 1.59-1.64 (m, 1H)[1.36-1.42 (m, 0.11H)], 1.22-1.25 (t, 3H) [1.17-1.20 (t, J=6.97,0.24H)].

Step 4: Synthesis of Methyl 4-[(2S,4S)-4-ethoxypiperidin-2-yl]benzoate(Compound of Formula (II)—R=Methyl)

To a 500 mL one neck flask was added the crude solution of step 3(above) in MTBE (telescoped from last step, 110 g, assay 10.52%, lightyellow solution, 43.95 mmol). The solution was concentrated to 18.4 gand the solvent was exchanged (JT=60° C.) with 55 g of n-heptane twiceto get 35 g yellow solution. The solution was transferred to 100 mL EasyMax equipped with impeller agitator. The solution was heated to 50° C.with 300 RPM, aged for 30 min, cooled to 41±2° C. and seed was added.The agitation was adjusted to low speed. The mixture was aged at 41±2°C. for 2 hours, cooled to 35±2° C. in 8-10 hours and then aged at 35±2°C. for 1-2 hours. n-heptane (7.9 g) was added dropwise. The agitationwas adjusted to medium speed. The mixture was cooled to IT=25±2° C. in 1hour and aged at 25±2° C. for 10-20 minutes. The mixture was filtered.The filtrate was re-charged to the reactor for rinsing the solid on thereactor wall. The mixture was filtered and the filter cake was washedwith pre-cooled (−5° C.) n-heptane (7.9 g). The cake was dried at 40° C.for 10 hours to afford 6.4 g of white solid (50% yield). ¹H NMR (400MHz, CDCl₃) δ (ppm)=7.99 (m, J=8.31 Hz, 2H), 7.45 (m, J=8.19 Hz, 2H),4.09 (dd, J=11.62, 2.20 Hz, 1H), 3.90 (s, 3H), 3.75 (t, J=2.81 Hz, 1H),3.53 (q, J=6.97 Hz, 2H), 3.17 (td, J=12.13, 2.63 Hz, 1H), 2.91-2.99 (m,1H), 1.99 (dd, J=13.57, 2.69 Hz, 1H), 1.88 (dt, J=13.79, 2.58 Hz, 1H),1.69-1.79 (m, 1H), 1.57-1.68 (m, 2H), 1.25 (t, J=7.03 Hz, 3H).

Example 4: Enantioselective Synthesis of Compound (S)-(C4) According tothe Following Sequence

Step 1: Synthesis of Benzyl 4-oxo-3,4-dihydropyridine-1(2H)-carboxylate(C6, Wherein P₁=Cbz and R=Methyl)

To a 2.0 L reactor, 4-methoxypyridine (C1, 45.0 g, 412.39 mmol, 1.0 eq)and methanol (900 mL) were added. The mixture was cooled to −75° C. withdry ice/acetone bath. A solution of benzyl chloroformate (73.86 g,432.99 mmol, 1.05 eq) in THF (90 mL) was charged dropwise while keepingIT≤−70° C. The reaction was stirred for 1 hour to afford a whitesuspension at −70° C. Sodium borohydride (16.38 g, 432.99 mmol, 1.05 eq)was added in portions while keeping IT≤−70° C. The reaction was stirredat −70° C. for 2 hours. Water (200 g) was added and the cooling bath wasremoved. A solution of 36% hydrogen chloride (16.72 g, 164.95 mmol, 0.4eq) in water (50 mL) was added in 10 min at 0-5° C. and stirred for 1hour. Then 20% Na₂CO₃ (85.5 g) was added to adjust pH=7 while maintainedIT≤5° C. Organic solvents were removed under vacuum. The resultingresidue was extracted with dichloromethane (450 mL). The dichloromethanephase was washed with 3 wt % hydrogen chloride (151 mL) and 3 wt %Na₂CO₃ (151 mL). After solvent exchange with MTBE, about 4 volume (180ml) of the MTBE mixture was obtained. The mixture was heated to 50° C.to afford a solution and then cooled to 45° C. Crystal seed of C6 wascharged and the mixture was aged at 40-45° C. for 7 hours. The mixturewas cooled to 10-15° C. in 3 hours. The white suspension was filteredand the wet cake was rinsed with cold MTBE (45 mL). The cake was driedunder vacuum at 40-50° C. for 2 hours to afford C6 as a white powder(91.56 g, 60% yield). ¹H NMR (400 MHz, CDCl₃): δ (ppm)=7.85 (br. s, 1H),7.37-7.43 (m, 5H), 5.43 (br. s, 1H), 5.26 (s, 2H), 4.05 (t, J=7.34 Hz,2H), 2.54-2.58 (m, 2H).

Step 2: Synthesis of Benzyl(S)-2-(4-(methoxycarbonyl)phenyl)-4-oxopiperidine-1-carboxylate ((S)-C4,Wherein P₁=Cbz and R=Methyl)

Method 1: A 500 ml Radleys reactor was purged 3 times with vacuum/N₂. C6(8 g, 34.60 mmol, 1.0 eq), C7 (9.34 g, 51.89 mmol, 1.5 eq), tert-Amylalcohol (160 mL) and deionized water (16 mL) were added. The mixture wasstirred for ≥40 minutes to give a clear colorless solution. The solutionwas purged 4 times with vacuum/N₂ and bubbled with N₂ via a syringeneedle for 1 hour. To the colorless solution was charged the mixed solidof (S)-XylBINAP (0.381 g, 0.519 mmol, 0.015 eq) and Rh(Acac)(C₂H₄)₂(0.134 g, 0.519 mmol, 0.015 eq). The mixture was continued to bubblewith N₂ for 15 minutes and purged 4 times with vacuum/N₂. The suspensionwas stirred for another 2 hours to dissolve (S)-XylBINAP. The reactionmixture was stirred at 55±4° C. for 15 hours. The reaction was followedby HPLC. The mixture was cooled and treated with 7.7% sodiumhypochlorite (1 g, 1.04 mmol, 0.03 eq) for 1.5 hours at 40±4° C.tert-Amyl alcohol was distilled off. The residue was extracted withisopropyl acetate (64 mL) and ethyl acetate (8 mL) and filtered. Theorganic phase was washed with 5% NaHCO₃ (50 g) then with 15% brine (40g) at 50±5° C. Some solvents were removed and ethyl acetate (21.6 g) wasadded. The solution was treated with Smopex-234 (1.2 g) at IT=55±5° C.for 2 hours then filtered via 200-300 mesh silica gel (1.6 g). Aftersolvent exchange with n-heptane, MTBE (44.4 g) was added. The mixturewas cooled to IT=42±3° C. (S)-C4 seed (10 mg) was added. The mixture wasaged for 2 hours and cooled to IT=31±3° C. in 3 hours. n-heptane (23.2g) was then charged in 1-2 hours. The mixture was aged for 2 hours andcooled to IT=20±3° C. in 2 hours. The mixture was filtered and the cakewas washed with a mixed solvent of MTBE (4.4 g) and n-heptane (4.1 g).Dried the wet cake at 60° C. for 5 hours to afford (S)-C4 (7.63 g, 60%yield) as yellow powder. ¹H NMR (400 MHz, CDCl₃): δ (ppm)=7.99 (d,J=8.44 Hz, 2H), 7.28-7.37 (m, 7H), 5.82 (br. s, 1H), 5.14-5.28 (m, 2H),4.30 (br. s, 1H), 3.91 (s, 3H), 3.22 (br. d, J=8.31 Hz, 1H), 2.84-3.03(m, 2H), 2.46-2.64 (m, 1H), 2.38 (br. d, J=16.26 Hz, 1H).

Method 2: To a 500 ml Radleys reactor purged 3 times with vacuum/N₂, C6(8 g, 34.60 mmol, 1.0 eq), C7 (9.34 g, 51.89 mmol, 1.5 eq), tert-Amylalcohol (160 mL) and deionized water (16 mL) were added. The mixture wasstirred for roughly 40 minutes to give a clear colorless solution. Thesolution was purged 4 times with vacuum/N₂ and bubbled with N₂ via asyringe needle for 1 hour. To the colorless solution, was charged themixed solid of (R, R)-Ph-BPE-Rh(Acac) (0.005 eq., 0.122 g, 0.173 mmol).The mixture was continued to bubble with N₂ for 15 minutes and purgedwith vacuum/N₂. The reaction mixture was stirred at 55±4° C. for 15hours. The reaction was followed by HPLC. Tert-amyl alcohol wasdistilled off. The residue was extracted with isopropyl acetate (64 mL)and ethyl acetate (8 mL), and then filtered. The organic phase waswashed with 5% NaHCO₃ (50 g), then with 15% brine (40 g) at 50±5° C.Some solvents were removed and ethyl acetate (21.6 g) was added. Thesolution was treated with Smopex-234 (1.2 g) at IT=55±5° C. for 2 hoursthen filtered via 200-300 mesh silica gel (1.6 g). After solventexchange with n-heptane, MTBE (44.4 g) was added. The mixture was cooledto IT=42±3° C. (S)-C4 seed (10 mg) was added. The mixture was aged for 2hours and cooled to IT=31±3° C. in 3 hours. n-heptane (23.2 g) was thencharged in 1-2 hours. The mixture was aged for 2 hours and cooled toIT=20±3° C. in 2 hours. The mixture was filtered and the cake was washedwith a mixed solvent of MTBE (4.4 g) and n-heptane (4.1 g). The wet cakewas dried at 60° C. for roughly 5 hours to afford (S)-C4 (10.17 g, 80%yield) as yellow powder. ¹H NMR (400 MHz, CDCl₃) δ (ppm)=7.99 (d, J=8.44Hz, 2H), 7.28-7.37 (m, 7H), 5.82 (br. s, 1H), 5.14-5.28 (m, 2H), 4.30(br. s, 1H), 3.91 (s, 3H), 3.22 (br. d, J=8.31 Hz, 1H), 2.84-3.03 (m,2H), 2.46-2.64 (m, 1H), 2.38 (br. d, J=16.26 Hz, 1H).

Method 3: To a 500 ml Radleys reactor purged 3 times with vacuum/N₂. C6(8 g, 34.60 mmol, 1.0 eq), C7 (9.34 g, 51.89 mmol, 1.5 eq), tert-amylalcohol (160 mL) and deionized water (16 mL) were added. The mixture wasstirred for roughly 40 minutes to give a clear colorless solution. Thesolution was purged 4 times with vacuum/N₂, and bubbled with N₂ via asyringe needle for 1 hour. To the colorless solution was charged themixed solid of (S)-XylBINAP-Rh(Acac) (0.01 eq., 0.324 g, 0.346 mmol).The mixture was continued to bubble with N₂ for 15 minutes and purgedwith vacuum/N₂. The reaction mixture was stirred at 55±4° C. for 15hours. The reaction was followed by HPLC. Tert-amyl alcohol wasdistilled off. The residue was extracted with isopropyl acetate (64 mL)and ethyl acetate (8 mL), and then filtered. The organic phase waswashed with 5% NaHCO₃ (50 g), then with 15% brine (40 g) at 50±5° C.Some solvents were removed and ethyl acetate (21.6 g) was added. Thesolution was treated with Smopex-234 (1.2 g) at IT=55±5° C. for 2 hoursthen filtered via 200-300 mesh silica gel (1.6 g). After solventexchange with n-heptane, MTBE (44.4 g) was added. The mixture was cooledto IT=42±3° C. (S)-C4 seed (10 mg) was added. The mixture was aged for 2hours and cooled to IT=31±3° C. in 3 hours. n-heptane (23.2 g) was thencharged in 1-2 hours. The mixture was aged for 2 hours and cooled toIT=20±3° C. in 2 hours. The mixture was filtered, and the cake waswashed with a mixed solvent of MTBE (4.4 g) and n-heptane (4.1 g). Thewet cake was dried at 60° C. for roughly 5 hours to afford (S)-C4 (10.30g, 81% yield) as yellow powder. ¹H NMR (400 MHz, CDCl₃) δ (ppm)=7.99 (d,J=8.44 Hz, 2H), 7.28-7.37 (m, 7H), 5.82 (br. s, 1H), 5.14-5.28 (m, 2H),4.30 (br. s, 1H), 3.91 (s, 3H), 3.22 (br. d, J=8.31 Hz, 1H), 2.84-3.03(m, 2H), 2.46-2.64 (m, 1H), 2.38 (br. d, J=16.26 Hz, 1H).

Example 5: Synthesis of Benzyl(2S,4S)-4-hydroxy-2-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate((S)-C5, Wherein P₁=Cbz and R=Methyl)

Preparation of 0.1 M PBS, pH 7.0, with 0.1% TPGS buffer solution: To a500 mL Radleys reactor equipped with impeller agitator was chargedNa₂HPO₄.12H₂O (8.63 g), NaH₂PO₄.2H₂O (2.41 g), Tap Water (388.6 g) andTPGS-750-M.001 (0.388 g). The mixture was stirred for ≥3 hours atIT=60±5° C. and then cooled to IT=51±3° C. 80 g of the buffer solutionwas taken from the reactor to a flask and cooled to ≤35° C. Check pHvalue of the buffer solution (7.0±0.5). To the above Radleys reactor(S)-C4 (20.0 g, 54.4 mmol, 1.0 eq), Isopropanol (16.36 g, 272.2 mmol,5.0 eq) and 0.1% TPGS buffer solution (60 g) were added. To a 25 mLflask was charged KRED-P3-G09 (0.4 g, #Codexis), NADP+ (0.1 g) and 0.1%TPGS buffer solution (60 g) from the above flask. All the solid wasdissolved. The solution of enzyme was charged to the 500 mL Reactor atIT=50±5° C. Rinsed the 25 mL flask with 0.1% TPGS buffer (10 g) andtransferred the solution to the 500 mL reactor at IT=50±5° C. Themixture was stirred with agitation speed 500 RPM at 51±3° C. for ≥8hours. The reaction was followed by HPLC. To the reactor 2-MeTHF (200mL) was added and the mixture was stirred for ≥60 minutes at 50±5° C.The mixture was held for ≥50 minutes without agitation and the bottomaqueous phase was separated. The organic phase was washed twice withanother 200 g of water at 50±5° C. The organic phase was concentrated toabout 70 g. After solvent exchange with twice 158 g acetonitrile to giveabout 80 g solution, which was cooled to <30° C. then filtered via MCC.MCC cake was washed with isopropyl acetate (40 mL/35.5 g) to afford(S)-05 in a light color solution (114.3 g, assay 16.95% 96.34% yield).The acetonitrile/isopropyl acetate solution was telescoped to the nextstep directly. ¹H NMR (400 MHz, CDCl₃): δ (ppm)=7.98 (d, J=8.44 Hz, 2H),7.23-7.38 (m, 7H), 5.61-5.72 (m, 1H), 5.18 (s, 2H), 4.23 (br. d, J=13.33Hz, 1H), 3.90 (s, 3H), 3.62-3.75 (m, 1H), 2.81 (td, J=13.51, 2.81 Hz,1H), 2.62 (br. d, J=13.33 Hz, 1H), 2.45 (br. s, 1H), 1.79-1.91 (m, 2H),1.41-1.56 (m, 1H).

Example 6: Asymmetric Synthesis of Methyl4-[(2S,4S)-4-ethoxypiperidin-2-yl]benzoate (Compound of Formula (II), ora Salt Thereof, —R=Methyl) According to the Following Sequence

Step 1: Synthesis of Benzyl(2S,4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-(methoxy carbonyl)Phenyl]piperidine-1-carboxylate ((S)-(C8), Wherein P₁=Cbz, P₂=TBS, andR=Methyl)

To a 500 ml Radleys Reactor was charged with (S)-05 solution (inacetonitrile/isopropyl acetate, 271.8 g, assay 14.72%, contained 40.0 gof (S)-05, 108.31 mmol, 1.0 eq) from the previous step. After solventexchange with isopropyl acetate (159.8 g/180 mL), 100 g clear solutionwas obtained. Isopropyl acetate (176 g/198 mL), imidazole (26.54 g,389.90 mmol, 3.6 eq) and TBS-Cl (27.75 g, 184.12 mmol, 1.7 eq) wereadded. The yellow suspension was stirred at 55±4° C. for 7 hours. Thereaction was followed by HPLC. The reaction mixture was cooled to 23±4°C. and filtered through MCC (2 g). The cake was washed with isopropylacetate (88.8 g/100 mL). 6% NaHCO₃ (240 g) was added and the mixture wasstirred for 20 minutes. The organic phase was washed with 5% brine(2×240 g) and concentrated to about 105 g. After solvent exchange withtoluene (120 g/135.4 mL), 105 g solution was obtained. Dichloromethane(298 g/224.5 mL) was added and the solution was filtered via 200-300mesh silica gel (4.4 g). The silica gel was eluted with another portionof dichloromethane (44 g/33 mL). The mother liquor was concentrated andthe solvent was exchanged with acetonitrile (2×280 mL, 442.4 g in total)to 100 g. The residue was diluted with acetonitrile (105 g/132.9 mL) toafford a light yellow solution (205 g, assay 25.55%, 100% yield), whichwas used for the next step directly. ¹H NMR (400 MHz, CDCl₃) δ(ppm)=8.01 (d, J=8.44 Hz, 2H), 7.23-7.37 (m, 7H), 5.60-5.70 (m, 1H),5.18 (s, 2H), 4.22 (br. d, J=13.45 Hz, 1H), 3.90 (s, 3H), 3.62-3.71 (m,1H), 2.82 (td, J=13.51, 2.81 Hz, 1H), 2.49 (br. d, J=13.45 Hz, 1H),1.83-1.96 (m, 1H), 1.75-1.80 (m, 1H), 1.47-1.60 (m, 1H), 0.86 (s, 9H),0.03 (s, 3H), 0.00 (s, 3H).

Step 2: Synthesis of Benzyl(2S,4S)-4-ethoxy-2-[4-(methoxycarbonyl)phenyl]piperidine-1-carboxylate((S)-C9, Wherein P₁=Cbz and R=Methyl)

To a 500 mL Radleys Reactor equipped with impeller agitator (S)-C8 in anacetonitrile solution (170.8 g, assay 29.28%, 103.38 mmol, 1.0 eq) andfresh acetonitrile (220 g) were charged, followed by Et₃SiH (36.06 g,310.13 mmol, 3.0 eq). The mixture was cooled to IT=4±5° C. and TESOTf(5.47 g, 20.68 mmol, 0.2 eq) was charged. To the mixture was charged asolution of 2,4,6-trimethyl-1,3,5-trioxane (13.66 g, 103.38 mmol, 1.0eq) in acetonitrile (23 g) over 60 minutes at IT=4±5° C. Upon addition,the mixture was stirred for 15 minutes. The reaction was followed byHPLC. To the reaction mixture was charged 5% aqueous sodium hydroxide(16.54 g, 20.68 mmol, 0.2 eq) and 20 g water, followed by n-heptane (60g). The mixture was stirred for 30 minutes at 20±5° C. The bottomacetonitrile phase was collected. To the acetonitrile phase was chargedwith MTBE (111 g) and 10% brine (300 g). The mixture was stirred for 30minutes. The upper MTBE phase was washed with 10% brine (2×300 g),concentrated to 90 g. MTBE (185 g) and water (150 g) were charged. Afterphase separation at 38±4° C. and solvent exchange of the organic layerwith isopropyl acetate (2×266.4 g), 205 g solution was obtained, whichwas filtered through Charcoal film slowly. The charcoal film was washedwith isopropyl acetate (22.2 g) to afford as a light yellow solution(223 g, 100% yield). The solution was telescoped to the next stepdirectly. ¹H NMR (400 MHz, CDCl₃) δ (ppm)=8.01 (d, J=8.44 Hz, 2H),7.25-7.38 (m, 7H), 5.68 (br. s, 1H), 5.19 (s, 2H), 4.27 (br. d, J=13.33Hz, 1H), 3.92 (s, 3H), 3.42-3.54 (m, 2H), 3.34 (ddd, J=10.88, 6.91, 4.22Hz, 1H), 2.84 (td, J=13.51, 2.81 Hz, 1H), 2.66 (br. d, J=13.20 Hz, 1H),1.96 (br. d, J=10.51 Hz, 1H), 1.75-1.90 (m, 1H), 1.33-1.53 (m, 1H), 1.18(t, J=6.97 Hz, 3H).

Step 3: Synthesis of Methyl 4-((2S,4S)-4-ethoxypiperidin-2-yl)benzoate(Compound of Formula (II), or a Salt Thereof—R=Methyl)

To a 500 mL autoclave which was purged with vacuum/N₂ (S)-C9 in anisopropyl acetate solution (278.4 g, assay 17.96%, 50 g of (S)-C9,125.80 mmol) and 10% Pd/C (5.0 g, 50% wet) were charged. The reactor waspurged with vacuum/H₂ and stirred for 7 hours at 25±5° C. The reactionwas followed by HPLC analysis. Filtered the reaction mixture via MCC(7.7 g) which was pre-washed with isopropyl acetate. Rinsed the reactorand MCC with isopropyl acetate (39 g). The mother liquor was combined toafford compound of formula (II) as a light yellow solution (315 g, assay10.0%, 95.1% yield). ¹H NMR (400 MHz, CDCl₃) δ (ppm)=7.99 (m, J=8.31 Hz,2H), 7.45 (m, J=8.19 Hz, 2H), 4.09 (dd, J=11.62, 2.20 Hz, 1H), 3.90 (s,3H), 3.75 (t, J=2.81 Hz, 1H), 3.53 (q, J=6.97 Hz, 2H), 3.17 (td,J=12.13, 2.63 Hz, 1H), 2.91-2.99 (m, 1H), 1.99 (dd, J=13.57, 2.69 Hz,1H), 1.88 (dt, J=13.79, 2.58 Hz, 1H), 1.69-1.79 (m, 1H), 1.57-1.68 (m,2H), 1.25 (t, J=7.03 Hz, 3H).

Step 4: Synthesis of the Maleic Salt of Compound of Formula (II)(R=Methyl)

To a 500 mL Radleys Reactor equipped with impeller agitator a solutionof methyl 4-((2S,4S)-4-ethoxypiperidin-2-yl)benzoate (381 g, assay10.03%, 145.12 mmol, 1.0 eq) from the previous step was charged. Thesolution was concentrated to 281 g and fresh isopropyl acetate (28.6 g)was added. Then a solution of maleic acid (8.45 g, 72.56 mmol, 0.5 eq)in acetone (30.5 mL) was added at 51±3° C. in 30 minutes. After stirringfor 15 minutes, a seed of the maleic salt of compound of formula (II)was added and the mixture was aged for 2 hours. A solution of maleicacid (8.45 g, 72.56 mmol, 0.5 eq) in acetone (30.5 mL) was charged at51±3° C. in 60 minutes and the mixture was aged for 2 hours. The mixturewas cooled to IT=10±3° C. in 6 hours and stirred for 120 minutes. Themixture was filtered and the filter cake was washed with pre-cooledisopropyl acetate (44.4 g). The cake was dried under high vacuum at 55°C. for 5-12 hours to afford maleic salt of compound of formula (II) aswhite solid (49.8 g, Yield 90.4%). ¹H NMR (400 MHz, CDCl₃) δ (ppm)9.35-9.78 (m, 2H), 8.02 (m, J=8.31 Hz, 2H), 7.58 (m, J=8.31 Hz, 2H),6.17 (s, 2H), 4.56 (br. d, J=11.13 Hz, 1H), 3.90 (s, 3H), 3.86 (s, 1H),3.48-3.57 (m, 2H), 3.38-3.44 (m, 2H), 2.42 (br. t, J=13.57 Hz, 1H),1.98-2.20 (m, 3H), 1.24 (t, J=6.97 Hz, 3H).

The maleic salt of compound of formula (II) may be characterized by ax-ray powder diffraction pattern (XRPD) comprising four or more 2Θvalues (CuKα λ=1.5418 Å) selected from the group consisting of 5.893,6.209, 11.704, 13.014, 16.403, 17.295, 17.592, 18.629, 18.942, 21.044,21.733, 21.737, 22.380, 23.528, 24.195, 26.013, 26.825, 29.017, 29.515,32.250, 35.069, 35.590, and 37.932, measured at a temperature of about22° C. and an x-ray wavelength, λ, of 1.5418 Å.

Example 7: Synthesis of Tert-butyl4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (Compound of Formula(III), or a Salt Thereof) According to the Following Sequence

Step 1: Synthesis of 7-methyl-1H-indol-5-ol (C11)

To a 250 mL flask equipped with a thermometer 3.4% Na₂HPO₄ (100 g,pH=8.91) was charged, followed by addition of Fremy's salt (4.84 g, 2.4eq). The mixture was stirred at 20±5° C. until a clear solution wasformed. A solution of 7-methylindoline in acetone (9.1 g, 11%) was addedin one portion. The mixture was stirred at 20±5° C. for 1.5 hours. Thensodium sulfite (0.38 g) was added. The mixture was extracted with ethylacetate (100 mL×2) The combined organic extracts were dried overanhydrous sodium sulfate, filtered and concentrated. To the residue 20mL acetonitrile was added. The solution was used directly in the nextstep.

Step 2: Synthesis of Tert-butyl5-hydroxy-7-methyl-1H-indole-1-carboxylate (C12, wherein P₃=Boc)

The above as prepared solution was cooled to 0±5° C. DMAP (0.34 g, 0.4eq) was charged followed by addition of (Boc)₂O (4.9 g, 3.0 eq). Themixture was warmed to 20±5° C., stirred at 20±5° C. for 30 minutes andconcentrated. To the residue was added methanol (40 mL). The mixture wascooled to 0±5° C. Potassium carbonate (5.1 g, 5.0 eq) was added. Themixture was stirred at 0±5° C. for 4 hours, warmed to 20±5° C. andstirred for additional 2 hours. The mixture was cooled to 0±5° C. Aceticacid (2 g) was added. pH was 7-8. The mixture was filtered and thefilter cake was washed with methanol (10 mL×2). The filtrate wasconcentrated and ethyl acetate (30 mL) was added. The mixture was washedwith water (20 mL) and 5% brine (20 mL). The organic layer wasconcentrated to afford a dark oil, which was slurried with (3:2)n-heptane:Ethyl acetate (5 g) to afford a yellow solid. The solid wascollected by filtration and dried to give C12 as yellow solid. 27.4%isolate yield from C10. ¹H-NMR (400 MHz, DMSO-d6): δ (ppm)=9.13 (s, 1H),7.52 (d, J=3.67 Hz, 1H), 6.74 (d, J=2.2 Hz, 1H), 6.56 (m, 1H), 6.50 (d,J=3.67 Hz, 1H), 2.45 (s, 3H), 1.57 (s, 9H). LCMS (m/z): positive mode248.1 [M]+, LCMS (m/z): negative mode 246.1 [M-1]−.

Step 3: Synthesis of Tert-butyl4-formyl-5-hydroxy-7-methyl-1H-indole-1-carboxylate (C13, WhereinP₃=Boc)

To a solution of tert-butyl 5-hydroxy-7-methyl-1H-indole-1-carboxylate(C12) (53.8% assay, 1.0 g, 2.2 mmol) in THF (20 mL) was added dropwisethe solution of CH₃MgBr in THF (1 N, 2.2 mL, 2.2 mmol). The resultingmixture was stirred at 20-25° C. for 10 minutes. (CHO)_(n) (0.2 g, 6.53mmol) was added to the mixture. The reaction mixture was heated to65-70° C. and stirred for 1 hours. The reaction mixture was cooled to20-25° C. Saturated NH₄Cl (20 mL) and MTBE (20 mL) were added. Themixture was separated and the aqueous layer was extracted with MTBE (20mL). The organic layers were combined and concentrated to give compoundC13 as yellow solid (0.7 g, 79% assay, 92% yield). ¹H-NMR (400 MHz,DMSO-d6) δ (ppm)=10.74 (s, 1H), 10.54 (s, 1H), 7.82 (d, J=4.0 Hz, 1H),7.34 (d, J=4.0 Hz, 1H), 6.81 (s, 1H), 2.59 (s, 3H), 1.65 (s, 9H). LCMS(m/z): positive mode 290.1 [M]+.

Step 4: Synthesis of Tert-Butyl4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (Compound of Formula(III))

To a solution of compound C13 (50 mg, 0.182 mmol) in dry DMF (3 mL) wasadded K₂CO₃ (50.2 mg, 0.363 mmol). The mixture was stirred for 10minutes and then dimethyl sulfate (25.2 mg, 0.20 mmol) was added. Thereaction mixture was stirred for 1 hours and poured into ice-water (12mL). The mixture was filtered and the filter cake was washed with water.The cake was dried under vacuum to give tert-Butyl4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (Compound of formula(III)) as pale solid (48 mg, 91% yield). ¹H-NMR (400 MHz, DMSO-d6) δ(ppm)=10.51 (s, 1H), 7.80 (d, J=4.0 Hz, 1H), 7.31 (d, J=4.0 Hz, 1H),6.81 (s, 1H), 3.95 (s, 3H), 2.61 (s, 3H), 1.59 (s, 9H). LCMS (m/z):negative mode 274.1 [M-1]−.

Example 8: Synthesis of Tert-butyl4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (Compound of Formula(III), or a Salt Thereof) According to the Following Sequence

Step 1: Synthesis of 5-(benzyloxy)-1,3-dimethyl-2-nitrobenzene

To a solution of commercially available 3,5-dimethyl-4-nitrophenol(100.0 g, 590.4 mmol) in DMF (500 mL), Cs₂CO₃ (230.8 g, 708.5 mmol) wasadded and the resulting mixture was stirred for 10 minutes. Then,(bromomethyl)benzene (104.1 g, 590.4 mmol) was added dropwise to themixture within 30 minutes. The reaction mixture was stirred at 20-25° C.for 1 hour, and then poured into ice-water (1800 mL). The solidseparated out was collected by filtration and washed with water (500mL). The cake was dissolved in ethyl acetate (500 mL) and the solutionwas washed with a saturated solution of NaCl (50 mL), was separated, andthe solution was concentrated to give5-(benzyloxy)-1,3-dimethyl-2-nitrobenzene 2 (147 g, 97.8% yield) asbrown solid. HPLC purity 99.7%. ¹H-NMR (400 MHz, DMSO-d6) δ (ppm)=7.42(m, 5H), 6.94 (s, 2H), 5.16 (s, 2H), 2.25 (s, 6H); LCMS (m/z): negativemode 256.2 [M-1]−

Step 2: Synthesis of Tert-butyl5-hydroxy-7-methyl-1H-indole-1-carboxylate (C12, Wherein P₃=Boc)

To a solution of 5-(benzyloxy)-1,3-dimethyl-2-nitrobenzene (60.0 g,233.2 mmol, from Step 1) in DMF (300 mL) were added DMF-DMA (87.8 g,699.6 mmol) and pyrrolidine (50.3 g, 699.6 mmol). The solution washeated to 85-90° C. and stirred for 19 hours under nitrogen, then themixture was cooled to 20-25° C. The volatile components (DMF-DMA,pyrrolidine and DMF) were removed at 65-70° C. on a rotary evaporator.The crude mixture was dissolved in ethyl acetate (300 mL), and RaneyNickel (6.0 g) was added. The reaction mixture was subjected tocatalytic hydrogenation under atmospheric pressure, overnight. Then, thereaction mixture was put under nitrogen. The mixture was filtrated andthe filtrate was concentrated to provide5-(benzyloxy)-7-methyl-1H-indole as a black oil.5-(benzyloxy)-7-methyl-1H-indole was used without further purificationinto the next step.

5-(benzyloxy)-7-methyl-1H-indole was dissolved in acetonitrile (300 mL),(Boc)₂O (53.6 g, 233.2 mmol) and DMAP (5.7 g, 46.6 mmol) were added. Thereaction mixture was stirred at 20-25° C. for 1 hour. Acetonitrile wasremoved on a rotary evaporator, and the residual mixture was dissolvedin ethyl acetate (300 mL). The solution was washed with a saturatedaqueous solution of NaHCO₃ and then concentrated to give a crude oilwhich was purified by column chromatography (SiO₂, 500 g) using amixture of heptane/MTBE (1:10) to provide the intermediate tert-butyl5-(benzyloxy)-7-methyl-1H-indole-1-carboxylate as a brown oil (42.1 g,49.2% yield). HPLC purity 93.5%. ¹H-NMR (400 MHz, DMSO-d6) δ (ppm)=7.59(d, J=3.67 Hz, 1H), 7.40 (m, 5H), 7.04 (d, J=2.45 Hz, 1H), 6.81 (d,J=2.2 Hz, 1H), 6.57 (d, J=3.67 Hz, 1H), 5.11 (s, 2H), 2.51 (s, 3H), 1.58(s, 9H). LCMS (m/z): negative mode 336.2 [M-1]−

To a solution of intermediate tert-butyl5-(benzyloxy)-7-methyl-1H-indole-1-carboxylate (36.7 g, 100 mmol) inethanol (250 mL), under nitrogen, 10% Pd/C (10.6 g, 10 mmol) andammonium formate (6.8 g, 105 mmol) were added. The solution was heatedto 45-50° C. and stirred for 5 hours under nitrogen. Then the mixturewas cooled to room temperature, filtered, and the filtrate wasconcentrated to give a residue oil. The residual oil was dissolved inethyl acetate (250 mL), the solution was washed with a saturated aqueoussolution of NaCl (100 mL), the phases were separated. The organic layerswere collected and concentrated. The obtained crude mixtures wasslurried with a (1:15) mixture of MTBE/Heptane (160 mL) for 2 hours. Theprecipitate was filtered and washed with heptane (50 mL). The cake wasdried under vacuum to give tert-butyl5-hydroxy-7-methyl-1H-indole-1-carboxylate (C12) as a tawny solid (21.8g, 87.2% yield). HPLC purity 97.7%. ¹H-NMR (400 MHz, DMSO-d6) δ(ppm)=9.13 (s, 1H), 7.52 (d, J=3.67 Hz, 1H), 6.74 (d, J=2.2 Hz, 1H),6.56 (m, 1H), 6.50 (d, J=3.67 Hz, 1H), 2.45 (s, 3H), 1.57 (s, 9H). LCMS(m/z): negative mode 246.2 [M-1]−

Step 3: Synthesis of Tert-butyl4-formyl-5-hydroxy-7-methyl-1H-indole-1-carboxylate (C13, WhereinP₃=Boc)

To a mixture of MgCl₂ (11.6 g, 119.7 mmol) and (CHO)n (5.0 g, 159.6mmol), in THF (150 ml), under nitrogen, triethylamine (17.8 mL, 127.7mmol) was added dropwise and the resulting mixture was stirred at 20-25°C. for 10 minutes. Then, tert-butyl5-hydroxy-7-methyl-1H-indole-1-carboxylate (C12) (10.0 g, 39.9 mmol) wasadded to the mixture. The reaction mixture was heated to 65-70° C. andstirred for 3 hours. The reaction mixture was cooled to 20-25° C.,followed by addition of 2N HCl (70 ml) and isopropyl acetate (150 ml).The mixture was separated and the organic layer was washed with a 5%NaCl solution. Then, the solution was concentrated to give a crudesolid. The solid was slurried with ethanol (100 mL) for 1 hour. Thesolid precipitate was filtrated, and washed with ethanol (20 mL). Thecake was dried under vacuum to give tert-butyl4-formyl-5-hydroxy-7-methyl-1H-indole-1-carboxylate (C13) as a tawnysolid (7.2 g, 63.9% yield). HPLC purity 96.5%. The filtrate solution wasconcentrated to 20 mL, then stirred for 1 hour. The solid was filtrated,and washed with ethanol (5 mL). The cake was dried by vacuum to give anadditional amount of tert-butyl4-formyl-5-hydroxy-7-methyl-1H-indole-1-carboxylate (C13) as a tawnysolid (1.1 g, 95.3% assay, 9.5% yield.). HPLC purity 90.5%. ¹H-NMR (400MHz, DMSO-d6) δ (ppm)=10.69 (s, 1H), 10.47 (s, 1H), 7.75 (d, J=3.35 Hz,1H), 7.27 (d, J=3.55 Hz, 1H), 6.74 (s, 1H), 2.51 (s, 3H), 1.59 (s, 9H);LCMS (m/z): negative mode 274.2 [M-1]-.

Step 4: Synthesis of Tert-Butyl4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (Compound of Formula(III))

To a suspension of tert-butyl4-formyl-5-hydroxy-7-methyl-1H-indole-1-carboxylate (C13) (6.0 g, 21.3mmol) in MeCN (60 mL), 50% K₂CO₃ solution (20 mL) and dimethyl sulfate(2.26 mL, 23.4 mmol) were added. The resulting mixture was stirred at35-40° C. for 3 hours. The reaction mixture was cooled to 20-25° C. andisopropyl acetate (30 mL) was added. The mixture was then extracted; thewater layer was extracted with isopropyl acetate (15 mL), the organiclayers were combined and concentrated to give a crude residual. Thecrude residual was dissolved in isopropyl acetate (60 mL), the solutionwas washed with a statured NH₄Cl solution, and then concentrated to givea crude product (6.6 g). The crude was slurried with ethylacetate/Heptane (100 mL, 1/50) for 3 hours. The solid was filtrated,washed with heptane (20 mL). The cake was dried under vacuum to givetert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (Compoundof formula (III)) as a pink solid (5.5 g, 87.8% yield). HPLC purity99.3%. ¹H-NMR (400 MHz, DMSO-d6) δ (ppm)=10.52 (s, 1H), 7.79 (d, J=3.67Hz, 1H), 7.31 (d, J=3.67 Hz, 1H), 7.02 (s, 1H), 3.95 (s, 3H), 2.61 (s,3H), 1.60 (s, 9H); LCMS (m/z): positive mode 290 [M]+.

Example 9: Synthesis of Compound of Formula (C15), or Salt Thereof(R=Methyl)

Method 1 (P₃=Boc and R=methyl): To a vessel were added Ir(CO)₂acac (1mg, 0.1 mol %), compound of formula (II) (maleic salt, 3 mmol, 1.137 g),compound of formula (III) (3 mmol, 0.867 g) in 9 mL of degassed ethanol.The autoclave was purged 3 times with nitrogen and 3 times with H₂ understirring (250 RPM). The reactions were run for 24 hours at 75° C. under20 bar of H₂ at 700 RPM. An aliquot of the reaction was diluted inmethanol and was analyzed by HPLC. Compound of formula (C15) wasobtained after 24 hours in 88% conversion.

Method 2 (P₃=Boc and R=methyl): To a vessel were added IrCl₃, xH₂O (0.05mol %, 0.9 mg, anhydrous), compound of formula (II) (maleic salt, 6mmol, 2.274 g), compound of formula (III) (6 mmol, 1.735 g) in 12 mL ofdegassed ethanol. The autoclave was purged 3 times with nitrogen and 3times with carbon monoxide (CO) (250 RPM). The autoclave was pressurizedwith 1 bar of CO and 19 bar of H₂ and run for 24 hours at 75° C. under20 bar of H₂/CO at 700 RPM. An aliquot of the reaction was diluted inmethanol and was analyzed by HPLC. Compound of formula (C15) wasobtained after 24 hours in 62% conversion.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.13 (d, J=8.16 Hz, 2H), 7.77 (br. d,J=7.84 Hz, 2H), 7.62-7.68 (m, 1H), 6.85 (s, 1H), 6.80 (d, J=3.76 Hz,1H), 4.01 (s, 3H), 3.92 (s, 3H), 3.73 (br. s, 1H), 3.55-3.67 (m, 4H),3.39-3.42 (m, 1H), 2.60-2.70 (m, 5H), 1.99-2.02 (br. d, 1H), 1.82-1.90(m, 2H), 1.74 (s, 9H), 1.64-1.70 (m, 1H), 1.35 (t, J=6.97 Hz, 3H).

1-16. (canceled)
 17. A process for preparing a compound of formula(C13),

or a salt thereof, wherein P₃ is a nitrogen protecting group, theprocess comprising the steps of reacting a compound of formula (C12),

or a salt thereof, wherein P₃ is a nitrogen protecting group; with aLewis acid or a base, in the presence of an aldehyde source; to obtainthe compound of formula (C13), or a salt thereof.
 18. The process ofclaim 17, wherein the Lewis acid is selected from the group consistingof MgCl₂, MgBr₂, and MgI₂ or mixtures thereof.
 19. The process of claim17, wherein the base is selected from the group consisting ofN,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene,1,4-diazabicyclo[2.2.2]octane, or mixtures thereof.
 20. The process ofclaim 17, wherein the aldehyde source is selected from the groupconsisting of formaldehyde, paraformaldehyde, and2,4,6-trimethyl-1,3,5-trioxane.
 21. The process of claim 17, wherein P₃is selected from the group consisting of tert-butyloxycarbonyl (Boc),toluenesulfonyl (tosyl), and trifluoromethanesulfonyl.
 22. A process forpreparing a compound of formula (III),

or a salt thereof, wherein P₃ is a protecting group; the processcomprising the steps of: (i) reacting a compound of formula (C12)

or a salt thereof, wherein P₃ is a nitrogen protecting group; with aLewis acid or a base, in the presence of an aldehyde source, to obtain acompound of formula (C13),

wherein P₃ is a nitrogen protecting group, and (ii) reacting thecompound of formula (C13), or a salt thereof, with an inorganic base, inthe presence of a methylating agent, to obtain the compound of formula(III), or a salt thereof.
 23. The process of claim 22, wherein the Lewisacid is selected from the group consisting of MgCl₂, MgBr₂, and MgI₂ ormixtures thereof.
 24. The process of claim 22, wherein the base isselected from the group consisting of N,N-diisopropylethylamine,1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, ormixtures thereof.
 25. The process of claim 22, wherein the aldehydesource is selected from the group consisting of formaldehyde,paraformaldehyde, and 2,4,6-trimethyl-1,3,5-trioxane.
 26. The process ofclaim 22, wherein P₃ is selected from the group consisting oftert-butyloxycarbonyl (Boc), toluenesulfonyl (tosyl), andtrifluoromethanesulfonyl.